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The IL-23/Th17 Axis in the Immunopathogenesis of Psoriasis

  • Author Footnotes
    3 These two authors contributed equally to this work
    Antonella Di Cesare
    Footnotes
    3 These two authors contributed equally to this work
    Affiliations
    St John's Institute of Dermatology, King's College London School of Medicine and NIHR Biomedical Research Centre, London, UK

    Department of Dermatology, University of L’Aquila, L’Aquila, Italy
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  • Author Footnotes
    3 These two authors contributed equally to this work
    Paola Di Meglio
    Footnotes
    3 These two authors contributed equally to this work
    Affiliations
    St John's Institute of Dermatology, King's College London School of Medicine and NIHR Biomedical Research Centre, London, UK
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  • Frank O. Nestle
    Correspondence
    Cutaneous Medicine and Immunotherapy, St John's Institute of Dermatology, King's College London School of Medicine at Guy's, Kings's College & St Thomas’ Hospitals, and NIHR Biomedical Research Centre Guy's and St Thomas’ Hospitals, Floor 9 Tower Wing, Guy's Hospital, London SE1 9RT, UK
    Affiliations
    St John's Institute of Dermatology, King's College London School of Medicine and NIHR Biomedical Research Centre, London, UK
    Search for articles by this author
  • Author Footnotes
    3 These two authors contributed equally to this work
      Abnormal production of inflammatory mediators is believed to play an important role in the pathogenesis of psoriasis. Emerging data, both in mice and in humans, put the spotlight on a new subset of T helper (Th) cells, in part characterized by their production of IL-17 and accordingly named Th17 cells. Here, we review the development, characterization, and function of human Th17 cells as well as the crucial role of IL-23 in the context of Th17-cell-dependent chronic inflammation in psoriasis. We further discuss recent clinical trials targeting the IL-23/Th17 axis in psoriasis.

      Abbreviations

      Ab
      antibody
      CD
      Crohn's disease
      CIA
      collagen-induced arthritis
      DCs
      dendritic cells
      EAE
      experimental autoimmune encephalomyelitis
      KC
      keratinocyte
      MS
      multiple sclerosis
      PASI
      psoriasis area and severity index
      RA
      rheumatoid arthritis
      STAT
      signal transducer and activator of transcription
      TGF
      transforming growth factor
      Th
      T helper
      TNF
      tumor necrosis factor

      Introduction

      Psoriasis is a chronic inflammatory skin disease, evolving over time during a complex interplay between environmental and genetic factors. Although, in the past, psoriasis has been considered a primary keratinocyte (KC) disorder, the successful treatment of psoriasis patients with cyclosporin A suggested a potential role of the immune system in the pathogenesis of the disease (
      • Mueller W.
      • Herrmann B.
      Cyclosporin A for psoriasis.
      ). The identification of activated CD4+ and CD8+ lymphocytes in psoriatic plaques and blood of psoriatic patients (
      • Bos J.D.
      • Hagenaars C.
      • Das P.K.
      • Krieg S.R.
      • Voorn W.J.
      • Kapsenberg M.L.
      Predominance of “memory” T cells (CD4+, CDw29+) over “naive” T cells (CD4+, CD45R+) in both normal and diseased human skin.
      ;
      • De Panfilis G.
      • Manara G.C.
      • Ferrari C.
      • Torresani C.
      • Zucchi A.
      • Devoto R.M.
      Further characterization of the “incipient lesion of chronic stationary type psoriasis vulgaris in exacerbation”. The CD4-positive lymphocytes are the prominent cell population infiltrating the dermis.
      ;
      • Ferenczi K.
      • Burack L.
      • Pope M.
      • Krueger J.G.
      • Austin L.M.
      CD69, HLA-DR and the IL-2R identify persistently activated T cells in psoriasis vulgaris lesional skin: blood and skin comparisons by flow cytometry.
      ), the detection of clonally expanded T cells (
      • Vollmer S.
      • Menssen A.
      • Prinz J.C.
      Dominant lesional T cell receptor rearrangements persist in relapsing psoriasis but are absent from nonlesional skin: evidence for a stable antigen-specific pathogenic T cell response in psoriasis vulgaris.
      ), and studies of human skin xenografts in mice (
      • Wrone-Smith T.
      • Nickoloff B.J.
      Dermal injection of immunocytes induces psoriasis.
      ;
      • Nickoloff B.J.
      • Wrone-Smith T.
      Injection of pre-psoriatic skin with CD4+ T cells induces psoriasis.
      ;
      • Boyman O.
      • Hefti H.P.
      • Conrad C.
      • Nickoloff B.J.
      • Suter M.
      • Nestle F.O.
      Spontaneous development of psoriasis in a new animal model shows an essential role for resident T cells and tumor necrosis factor-alpha.
      ) supported the growing evidence that activated T cells are the primary modulators in the pathogenesis of psoriasis. Clinical studies on the therapeutic efficacy of T-cell-targeted drugs further substantiated the role of T cells in psoriasis (
      • Abrams J.R.
      • Kelley S.L.
      • Hayes E.
      • Kikuchi T.
      • Brown M.J.
      • Kang S.
      • et al.
      Blockade of T lymphocyte costimulation with cytotoxic T lymphocyte-associated antigen 4-immunoglobulin (CTLA4Ig) reverses the cellular pathology of psoriatic plaques, including the activation of keratinocytes, dendritic cells, and endothelial cells.
      ;
      • Goedkoop A.Y.
      • de Rie M.A.
      • Picavet D.I.
      • Kraan M.C.
      • Dinant H.J.
      • van Kuijk A.W.
      • et al.
      Alefacept therapy reduces the effector T-cell population in lesional psoriatic epidermis.
      ). Characterization of cells and cytokines involved in the initiation and maintenance of psoriasis showed elevated levels of IFN-γ, tumor necrosis factor (TNF) -α, and IL -12, but not IL-4, IL-5, or IL-10, at both mRNA and protein levels (
      • Nestle F.O.
      • Turka L.A.
      • Nickoloff B.J.
      Characterization of dermal dendritic cells in psoriasis. Autostimulation of T lymphocytes and induction of Th1 type cytokines.
      ;
      • Schlaak J.F.
      • Buslau M.
      • Jochum W.
      • Hermann E.
      • Girndt M.
      • Gallati H.
      • et al.
      T cells involved in psoriasis vulgaris belong to the Th1 subset.
      ;
      • Austin L.M.
      • Ozawa M.
      • Kikuchi T.
      • Walters I.B.
      • Krueger J.G.
      The majority of epidermal T cells in Psoriasis vulgaris lesions can produce type 1 cytokines, interferon-gamma, interleukin-2, and tumor necrosis factor-alpha, defining TC1 (cytotoxic T lymphocyte) and TH1 effector populations: a type 1 differentiation bias is also measured in circulating blood T cells in psoriatic patients.
      ). These observations led to the new definition of psoriasis as a T helper (Th) 1-type disease (
      • Lew W.
      • Bowcock A.M.
      • Krueger J.G.
      Psoriasis vulgaris: cutaneous lymphoid tissue supports T-cell activation and “Type 1” inflammatory gene expression.
      ).
      Recently, a new population of IL-17-producing Th cells, accordingly named Th17, has been described and its involvement in model systems of autoimmunity shown (
      • Weaver C.T.
      • Hatton R.D.
      • Mangan P.R.
      • Harrington L.E.
      IL-17 family cytokines and the expanding diversity of effector T cell lineages.
      ). Furthermore, the development and maintenance of Th17 cells have been linked to IL-23, a key initiating cytokine in the development of autoimmunity (
      • Bettelli E.
      • Oukka M.
      • Kuchroo V.K.
      T(H)-17 cells in the circle of immunity and autoimmunity.
      ;
      • Kastelein R.A.
      • Hunter C.A.
      • Cua D.J.
      Discovery and biology of IL-23 and IL-27: related but functionally distinct regulators of inflammation.
      ).
      The findings of elevated levels of IL-23 and Th17-related cytokines in cutaneous lesions and in the serum of psoriatic patients, the association of IL23R gene variants with psoriasis, and the evidence of a functional role of Th17 cells in autoimmunity, provide the basis for a rising interest in the IL-23/Th17 axis in psoriasis (
      • Blauvelt A.
      T-helper 17 cells in psoriatic plaques and additional genetic links between IL-23 and psoriasis.
      ). In this review, we will discuss the biology and function of the IL-23/Th17 pathway, its potential dysregulation in psoriasis, and the exciting perspective of novel therapeutics targeting the IL-23/Th17 axis.

      Biology Of Il-23 And Th17 Cells

      IL-23 and the IL-23 receptor

      IL-23 was discovered in 2000 by Oppmann and co-workers while searching sequence databases for members of the IL-6 cytokine family (
      • Oppmann B.
      • Lesley R.
      • Blom B.
      • Timans J.C.
      • Xu Y.
      • Hunte B.
      • et al.
      Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12.
      ). They identified a new protein designed as IL-23p19, which had no biological activity but, when combined with the IL-12p40 subunit of IL-12, formed a novel heterodimeric cytokine that they named IL-23.
      IL-23 was found to be expressed by activated mouse and human monocytes, macrophages, dendritic cells (DCs), T cells, B cells, and endothelial cells (
      • Oppmann B.
      • Lesley R.
      • Blom B.
      • Timans J.C.
      • Xu Y.
      • Hunte B.
      • et al.
      Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12.
      ;
      • Pirhonen J.
      • Matikainen S.
      • Julkunen I.
      Regulation of virus-induced IL-12 and IL-23 expression in human macrophages.
      ). IL-23 binds to and signals through its heterodimeric receptor complex composed of IL-12Rβ1 and IL-23R subunits (
      • Parham C.
      • Chirica M.
      • Timans J.
      • Vaisberg E.
      • Travis M.
      • Cheung J.
      • et al.
      A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R.
      ) (Figure 1). Whereas IL-12Rβ1 is also part of the IL-12 receptor, IL-23R is unique to the IL-23 receptor complex. IL-23R expression on memory T cells, natural killer T cells, monocytes, and DCs correlates with cellular responsiveness to IL-23 (
      • Belladonna M.L.
      • Renauld J.C.
      • Bianchi R.
      • Vacca C.
      • Fallarino F.
      • Orabona C.
      • et al.
      IL-23 and IL-12 have overlapping, but distinct, effects on murine dendritic cells.
      ;
      • Parham C.
      • Chirica M.
      • Timans J.
      • Vaisberg E.
      • Travis M.
      • Cheung J.
      • et al.
      A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R.
      ;
      • Rachitskaya A.V.
      • Hansen A.M.
      • Horai R.
      • Li Z.
      • Villasmil R.
      • Luger D.
      • et al.
      Cutting edge: NKT cells constitutively express IL-23 receptor and RORgammat and rapidly produce IL-17 upon receptor ligation in an IL-6-independent fashion.
      ).
      Figure thumbnail gr1
      Figure 1IL-23 signaling pathway. IL-23 is a heterodimeric cytokine composed of p40 and p19 subunits. It binds to its IL-23 receptor complex composed of IL-12Rβ1 and IL-23R subunits, which are associated with the Jak family members, Tyk2 and Jak2, respectively. IL-23 binding to its receptor complex results in Jak2-mediated phosphorylation of tyrosine residues located in the intracellular domain of the IL-23R subunit. Phosphorylated tyrosine residues serve as a docking site for STAT3 molecules, which in turn get phosphorylated. Phospho-STAT3 proteins homodimerize and translocate into the nucleus inducing transcription of cytokines, such as IL-17A, IL-17F, IL-22 and IFN-γ. Amino acid substitutions, arginine to glutamine (R381Q) and leucine to proline (L310P), in the IL-23R subunit, conferring protection against psoriasis, are shown.
      Both the IL-12Rβ1 and IL-23R chain lack intrinsic signaling activity and are associated with intracellular proteins to induce downstream signaling. IL-12Rβ1 binds to the Jak family member, Tyk2, whereas IL-23R associates with Jak2 (
      • Zou J.
      • Presky D.H.
      • Wu C.Y.
      • Gubler U.
      Differential associations between the cytoplasmic regions of the interleukin-12 receptor subunits beta1 and beta2 and JAK kinases.
      ;
      • Parham C.
      • Chirica M.
      • Timans J.
      • Vaisberg E.
      • Travis M.
      • Cheung J.
      • et al.
      A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R.
      ). IL-23 stimulation results in ligand-induced autophosphorylation and transphosphorylation of receptor-associated Jaks. Jaks in turn phosphorylate tyrosine residues located in the intracellular domain of the receptor subunits. These phosphorylated tyrosine residues serve as docking sites for the signal transducer and activator of transcription (STAT) molecules, which in turn also get phosphorylated. Notably, IL-23 activates a similar spectrum of STATs as IL-12: STAT1, STAT3, STAT4, and STAT5 (
      • Parham C.
      • Chirica M.
      • Timans J.
      • Vaisberg E.
      • Travis M.
      • Cheung J.
      • et al.
      A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R.
      ); however, STAT3 is the main player in the IL-23 signaling pathway, whereas STAT4 is the main player in the IL-12 pathway. Once activated, STAT3 homodimers translocate into the nucleus, where they bind to the DNA in the promoter region of the target genes.
      Since its discovery, IL-23 has been linked to the pathogenesis of autoimmune inflammation. Early studies showed that expression of IL-23p19 in multiple tissues of transgenic mice induced systemic inflammation, runting, infertility, and premature death (
      • Wiekowski M.T.
      • Leach M.W.
      • Evans E.W.
      • Sullivan L.
      • Chen S.C.
      • Vassileva G.
      • et al.
      Ubiquitous transgenic expression of the IL-23 subunit p19 induces multiorgan inflammation, runting, infertility, and premature death.
      ). Interestingly, mice lacking IL-23p19 and IL-12p40 subunits, but not those lacking the IL-12p35-specific subunit, are resistant to animal models of autoimmunity, including experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA) (
      • Cua D.J.
      • Sherlock J.
      • Chen Y.
      • Murphy C.A.
      • Joyce B.
      • Seymour B.
      • et al.
      Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain.
      ;
      • Murphy C.A.
      • Langrish C.L.
      • Chen Y.
      • Blumenschein W.
      • McClanahan T.
      • Kastelein R.A.
      • et al.
      Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation.
      ). Furthermore, the development of spontaneous colitis in IL-10-deficient mice is completely prevented by crossing them with IL-23p19-deficient mice (
      • Yen D.
      • Cheung J.
      • Scheerens H.
      • Poulet F.
      • McClanahan T.
      • McKenzie B.
      • et al.
      IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6.
      ). These data, together with the observation that IFN-γ-producing cells are present in EAE-resistant, IL-23-deficient mice (
      • Langrish C.L.
      • Chen Y.
      • Blumenschein W.M.
      • Mattson J.
      • Basham B.
      • Sedgwick J.D.
      • et al.
      IL-23 drives a pathogenic T cell population that induces autoimmune inflammation.
      ), showed that IL-23-driven immune responses are IFN-γ pathway independent and that IL-23, rather than IL-12, is critical for the development of autoimmune disease in these model systems. The expression of IL-23p19 in clinical samples of Crohn's disease (CD) (
      • Schmidt C.
      • Giese T.
      • Ludwig B.
      • Mueller-Molaian I.
      • Marth T.
      • Zeuzem S.
      • et al.
      Expression of interleukin-12-related cytokine transcripts in inflammatory bowel disease: elevated interleukin-23p19 and interleukin-27p28 in Crohn's disease but not in ulcerative colitis.
      ), rheumatoid arthritis (RA) (
      • Sato K.
      • Suematsu A.
      • Okamoto K.
      • Yamaguchi A.
      • Morishita Y.
      • Kadono Y.
      • et al.
      Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction.
      ), and multiple sclerosis (MS) patients (
      • Vaknin-Dembinsky A.
      • Balashov K.
      • Weiner H.L.
      IL-23 is increased in dendritic cells in multiple sclerosis and down-regulation of IL-23 by antisense oligos increases dendritic cell IL-10 production.
      ;
      • Li Y.
      • Chu N.
      • Hu A.
      • Gran B.
      • Rostami A.
      • Zhang G.X.
      Increased IL-23p19 expression in multiple sclerosis lesions and its induction in microglia.
      ,
      • Li Y.
      • Chu N.
      • Hu A.
      • Gran B.
      • Rostami A.
      • Zhang G.X.
      Inducible IL-23p19 expression in human microglia via p38 MAPK and NF-kappaB signal pathways.
      ) supports a possible role of IL-23 in common human autoimmune diseases.
      Robust evidence for a role of the IL-23 pathway in autoimmune diseases comes from recent genetic studies. Taking advantage of recently introduced high-throughput genotyping technologies, a number of genome-wide association studies have been carried out to identify novel susceptibility genes for common complex genetic diseases. We and others have conducted such studies in psoriasis and have identified a non-synonymous nucleotide substitution in exon 9 of the IL23R gene, which results in an arginine to glutamine exchange (Arg381Gln) in the cytoplasmic domain of the receptor, showing a protective role of the variant against psoriasis (
      • Capon F.
      • Di Meglio P.
      • Szaub J.
      • Prescott N.J.
      • Dunster C.
      • Baumber L.
      • et al.
      Sequence variants in the genes for the interleukin-23 receptor (IL23R) and its ligand (IL12B) confer protection against psoriasis.
      ;
      • Cargill M.
      • Schrodi S.J.
      • Chang M.
      • Garcia V.E.
      • Brandon R.
      • Callis K.P.
      • et al.
      A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes.
      ;
      • Nair R.P.
      • Ruether A.
      • Stuart P.E.
      • Jenisch S.
      • Tejasvi T.
      • Hiremagalore R.
      • et al.
      Polymorphisms of the IL12B and IL23R genes are associated with psoriasis.
      ). The same effect has also been clearly documented in CD, ulcerative colitis, (
      • Duerr R.H.
      • Taylor K.D.
      • Brant S.R.
      • Rioux J.D.
      • Silverberg M.S.
      • Daly M.J.
      • et al.
      A genome-wide association study identifies IL23R as an inflammatory bowel disease gene.
      ), ankylosing spondylitis (
      • Rueda B.
      • Orozco G.
      • Raya E.
      • Fernandez-Sueiro J.L.
      • Mulero J.
      • Blanco F.J.
      • et al.
      The IL23R Arg381Gln non-synonymous polymorphism confers susceptibility to ankylosing spondylitis.
      ), graft-versus-host disease (
      • Elmaagacli A.H.
      • Koldehoff M.
      • Landt O.
      • Beelen D.W.
      Relation of an interleukin-23 receptor gene polymorphism to graft-versus-host disease after hematopoietic-cell transplantation.
      ), and, with less significant results, also in celiac disease and MS (
      • Nunez C.
      • Dema B.
      • Cenit M.C.
      • Polanco I.
      • Maluenda C.
      • Arroyo R.
      • et al.
      IL23R: a susceptibility locus for celiac disease and multiple sclerosis?.
      ). Additional variants in the IL23R gene have been associated with psoriasis (
      • Cargill M.
      • Schrodi S.J.
      • Chang M.
      • Garcia V.E.
      • Brandon R.
      • Callis K.P.
      • et al.
      A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes.
      ;
      • Nair R.P.
      • Ruether A.
      • Stuart P.E.
      • Jenisch S.
      • Tejasvi T.
      • Hiremagalore R.
      • et al.
      Polymorphisms of the IL12B and IL23R genes are associated with psoriasis.
      ), RA (
      • Farago B.
      • Magyari L.
      • Safrany E.
      • Csongei V.
      • Jaromi L.
      • Horvatovich K.
      • et al.
      Functional variants of interleukin-23 receptor gene confer risk for rheumatoid arthritis but not for systemic sclerosis.
      ), Graves’ disease (
      • Huber A.K.
      • Jacobson E.M.
      • Jazdzewski K.
      • Concepcion E.S.
      • Tomer Y.
      Interleukin (IL)-23 receptor is a major susceptibility gene for Graves’ ophthalmopathy: the IL-23/T-helper 17 axis extends to thyroid autoimmunity.
      ), and MS (
      • Illes Z.
      • Safrany E.
      • Peterfalvi A.
      • Magyari L.
      • Farago B.
      • Pozsonyi E.
      • et al.
      3′UTR C2370A allele of the IL-23 receptor gene is associated with relapsing-remitting multiple sclerosis.
      ), thus suggesting that variants in the IL23R gene, may be common determinants of autoimmunity. In addition, we and others have also shown that the IL12B gene, coding for the IL-12p40 subunit of IL-12 and IL-23, is associated with psoriasis (
      • Capon F.
      • Di Meglio P.
      • Szaub J.
      • Prescott N.J.
      • Dunster C.
      • Baumber L.
      • et al.
      Sequence variants in the genes for the interleukin-23 receptor (IL23R) and its ligand (IL12B) confer protection against psoriasis.
      ;
      • Cargill M.
      • Schrodi S.J.
      • Chang M.
      • Garcia V.E.
      • Brandon R.
      • Callis K.P.
      • et al.
      A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes.
      ).

      Th17 cells and cytokines

      Initial studies showed that IL-23 is involved in the proliferation of human and murine memory T cells (
      • Oppmann B.
      • Lesley R.
      • Blom B.
      • Timans J.C.
      • Xu Y.
      • Hunte B.
      • et al.
      Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12.
      ); in contrast, naïve T cells do not respond to IL-23 as they express little or no IL-23R subunit (
      • Parham C.
      • Chirica M.
      • Timans J.
      • Vaisberg E.
      • Travis M.
      • Cheung J.
      • et al.
      A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R.
      ). Subsequent studies showed that IL-23 promotes the expansion of the novel Th17 population characterized by the production of IL-17A and other related proinflammatory cytokines (
      • Aggarwal S.
      • Ghilardi N.
      • Xie M.H.
      • de Sauvage F.J.
      • Gurney A.L.
      Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17.
      ;
      • Harrington L.E.
      • Hatton R.D.
      • Mangan P.R.
      • Turner H.
      • Murphy T.L.
      • Murphy K.M.
      • et al.
      Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages.
      ;
      • Langrish C.L.
      • Chen Y.
      • Blumenschein W.M.
      • Mattson J.
      • Basham B.
      • Sedgwick J.D.
      • et al.
      IL-23 drives a pathogenic T cell population that induces autoimmune inflammation.
      ;
      • Park H.
      • Li Z.
      • Yang X.O.
      • Chang S.H.
      • Nurieva R.
      • Wang Y.H.
      • et al.
      A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17.
      ). CD4+ Th cells are essential regulators of adaptive immune responses and inflammatory diseases. After activation by professional antigen-presenting cells, antigen-specific CD4+ T cells differentiate into effector cells according to the cytokine milieu, and specialize in terms of their secreted cytokines. Th1 cells produce IFN-γ as well as lymphotoxin, and are involved in cell-mediated immunity against intracellular bacteria and viruses. Their development from naïve T cells depends on the presence of IL-12 and on the activation of the master regulator transcription factor, T-bet. Th2 cells produce IL-4, IL-5, IL-13, and IL-25 (IL-17E), and are implicated in humoral immunity against parasites and helminthes. IL-4 and the transcription factor GATA-3 are the key regulators of Th2 differentiation. Interestingly, each subset promotes its own development, whereas it inhibits that of other subsets through cytokine secretion. Immune activation that results from dysregulated Th1 responses to self or commensal antigens can promote autoimmune-type tissue destruction, whereas dysregulated Th2 responses can cause allergy and asthma.
      Th17 cells represent the first new lineage of effector CD4+ T cells to be described since the original report of Th1 and Th2 subtypes by
      • Mosmann T.R.
      • Cherwinski H.
      • Bond M.W.
      • Giedlin M.A.
      • Coffman R.L.
      Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins.
      (Figure 2). IL-17A was originally described as a product of activated memory CD4+ T cells (
      • Fossiez F.
      • Djossou O.
      • Chomarat P.
      • Flores-Romo L.
      • Ait-Yahia S.
      • Maat C.
      • et al.
      T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines.
      ), but
      • Infante-Duarte C.
      • Horton H.F.
      • Byrne M.C.
      • Kamradt T.
      Microbial lipopeptides induce the production of IL-17 in Th cells.
      provided a first indication in 2000 that IL-17A-producing cells cannot be categorized according to the classical Th1/Th2 paradigm. In fact they showed that CD4+ T cells, primed with a synthetic peptide in the presence of the spirochete Borrelia burgdorferi, express IL-17A at significantly higher levels than do CD4+ T cells primed in the presence of IL-12, whereas Th2 cytokines, IL-4 and IL-10, were inhibited under the same conditions (
      • Infante-Duarte C.
      • Horton H.F.
      • Byrne M.C.
      • Kamradt T.
      Microbial lipopeptides induce the production of IL-17 in Th cells.
      ). The concept that the IL-17-producing T cell may be of a distinct T-cell lineage was further strengthened by the discovery of the IL-23 function (
      • Aggarwal S.
      • Ghilardi N.
      • Xie M.H.
      • de Sauvage F.J.
      • Gurney A.L.
      Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17.
      ) and by gene-targeted mice studies. In IL-23-deficient mice, CIA and EAE resistance correlates well with the absence of IL-17-producing T cells, despite normal induction of IFN-γ-producing Th1 cells, thus suggesting that the former are essential for the establishment of autoimmunity (
      • Murphy C.A.
      • Langrish C.L.
      • Chen Y.
      • Blumenschein W.
      • McClanahan T.
      • Kastelein R.A.
      • et al.
      Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation.
      ;
      • Langrish C.L.
      • Chen Y.
      • Blumenschein W.M.
      • Mattson J.
      • Basham B.
      • Sedgwick J.D.
      • et al.
      IL-23 drives a pathogenic T cell population that induces autoimmune inflammation.
      ). Finally, the gene expression analysis of IL-17-producing cells identified a unique expression pattern of proinflammatory mediators, including IL-17A, IL-17F, IL-6, CCL20, and GM-CSF (
      • Langrish C.L.
      • Chen Y.
      • Blumenschein W.M.
      • Mattson J.
      • Basham B.
      • Sedgwick J.D.
      • et al.
      IL-23 drives a pathogenic T cell population that induces autoimmune inflammation.
      ). Definitive arguments pointing toward IL-17-producing cells as a distinct T-cell lineage arose simultaneously from two laboratories, showing that the development of murine Th17 cells from naïve T cells is potently inhibited by IFN-γ and IL-4 (
      • Harrington L.E.
      • Hatton R.D.
      • Mangan P.R.
      • Turner H.
      • Murphy T.L.
      • Murphy K.M.
      • et al.
      Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages.
      ;
      • Park H.
      • Li Z.
      • Yang X.O.
      • Chang S.H.
      • Nurieva R.
      • Wang Y.H.
      • et al.
      A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17.
      ). During recent years, cytokines and signaling pathways involved in Th17 differentiation have been widely investigated in both mice and humans. Expanding the initial in vivo observations (
      • Aggarwal S.
      • Ghilardi N.
      • Xie M.H.
      • de Sauvage F.J.
      • Gurney A.L.
      Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17.
      ;
      • Cua D.J.
      • Sherlock J.
      • Chen Y.
      • Murphy C.A.
      • Joyce B.
      • Seymour B.
      • et al.
      Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain.
      ;
      • Langrish C.L.
      • Chen Y.
      • Blumenschein W.M.
      • Mattson J.
      • Basham B.
      • Sedgwick J.D.
      • et al.
      IL-23 drives a pathogenic T cell population that induces autoimmune inflammation.
      ), it has been shown later that, in mice, IL-23 alone is not sufficient to drive in vitro Th17 differentiation from naïve T cells as they do not express IL-23R; rather, it acts on the already committed Th17 population. In fact, transforming growth factor (TGF)-β1, together with IL-6, IL-21, and subsequently IL-23, promotes differentiation of Th17 cells from naïve CD4+ T cells (
      • Bettelli E.
      • Carrier Y.
      • Gao W.
      • Korn T.
      • Strom T.B.
      • Oukka M.
      • et al.
      Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells.
      ;
      • Mangan P.R.
      • Harrington L.E.
      • O’Quinn D.B.
      • Helms W.S.
      • Bullard D.C.
      • Elson C.O.
      • et al.
      Transforming growth factor-beta induces development of the T(H)17 lineage.
      ;
      • Veldhoen M.
      • Hocking R.J.
      • Atkins C.J.
      • Locksley R.M.
      • Stockinger B.
      TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells.
      ;
      • Korn T.
      • Bettelli E.
      • Gao W.
      • Awasthi A.
      • Jager A.
      • Strom T.B.
      • et al.
      IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells.
      ). This finding was initially surprising as TGF-β1 is known to induce the development of regulatory T cells with a potent suppressor function (
      • Chen W.
      • Jin W.
      • Hardegen N.
      • Lei K.J.
      • Li L.
      • Marinos N.
      • et al.
      Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3.
      ). Consistent with their definition as a bona fide distinct T-cell lineage, the development of Th17 cells does not involve any of the transcription factors implicated in Th1/Th2 differentiation. On the contrary, both in vitro and in vivo differentiation of Th17 cells required the TGF-β1-induced upregulation of the unique lineage-specific transcription factor, ROR (retinoid-related orphan receptor)γt, an orphan nuclear receptor (
      • Ivanov I.I.
      • McKenzie B.S.
      • Zhou L.
      • Tadokoro C.E.
      • Lepelley A.
      • Lafaille J.J.
      • et al.
      The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells.
      ;
      • Zhou L.
      • Ivanov I.I.
      • Spolski R.
      • Min R.
      • Shenderov K.
      • Egawa T.
      • et al.
      IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways.
      ). Furthermore, activation of STAT3 (
      • Mathur A.N.
      • Chang H.C.
      • Zisoulis D.G.
      • Stritesky G.L.
      • Yu Q.
      • O’Malley J.T.
      • et al.
      Stat3 and Stat4 direct development of IL-17-secreting Th cells.
      ;
      • Yang X.O.
      • Panopoulos A.D.
      • Nurieva R.
      • Chang S.H.
      • Wang D.
      • Watowich S.S.
      • et al.
      STAT3 regulates cytokine-mediated generation of inflammatory helper T cells.
      ), as well as involvement of the orphan nuclear receptor RORα (
      • Yang X.O.
      • Pappu B.P.
      • Nurieva R.
      • Akimzhanov A.
      • Kang H.S.
      • Chung Y.
      • et al.
      T helper 17 lineage differentiation is programmed by orphan nuclear receptors RORalpha and RORgamma.
      ) and of the aryl hydrocarbon receptor (
      • Quintana F.J.
      • Basso A.S.
      • Iglesias A.H.
      • Korn T.
      • Farez M.F.
      • Bettelli E.
      • et al.
      Control of T(reg) and T(H)17 cell differentiation by the aryl hydrocarbon receptor.
      ;
      • Veldhoen M.
      • Hirota K.
      • Westendorf A.M.
      • Buer J.
      • Dumoutier L.
      • Renauld J.C.
      • et al.
      The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins.
      ) have been suggested to be important in Th17 development.
      Figure thumbnail gr2
      Figure 2Model for T helper (Th) or T regulatory (Treg) differentiation from naïve CD4+ T cells. Th1 cells differentiate in the presence of IL-12, and require activation of the master regulator transcription factor, T-bet, through STAT1. Fully committed Th1 cells express chemokine receptors, CXCR6, CXCR3, and CCR5, and produce IFN-γ and lymphotoxin through STAT4. They are involved in cell-mediated immunity against intracellular bacteria and viruses. Th2 cells depend on the presence of IL-4, STAT6, and GATA-3, and release IL-4, IL-5, IL-13, and IL-25. Th2 cells express chemokine receptors, CCR3, CCR4, and CCR8, and are important in humoral immunity against parasites and helminthes. Th17 cells require a combination of TGF-β1 and proinflammatory cytokines (IL-1β, IL-6, and/or IL-21) to differentiate from naïve CD4+, and RORC-(variant) 2 acts as the key transcriptional regulator. Upregulation of the IL-23 receptor makes these cells responsive to IL-23. Human Th17 cells produce, for example, IL-17A, IL-17F, IL-22, and IL-26, and are important in host protection against extracellular pathogens and in autoimmunity. Their surface markers include chemokine receptors, CCR4, CCR6, and CD161 (not shown). In addition to effector T cells, naïve CD4+ T cells can also differentiate into induced Treg (iTreg) in the presence of IL-2 and TGF-β1 or IL-10. iTreg produces immunosuppressive cytokines, TGF-β1, IL-10, and IL-35, and express surface markers, GITR, CD25, and CLTA-4. Similar to thymus-derived naturally occurring Treg (nTreg, not shown), iTreg also expresses the master regulator transcription factor, Foxp3.
      A paucity of data regarding Th17 differentiation in humans has been recently rectified by several publications addressing key issues pertinent to possible differences between mouse and human Th17 biology (
      • Chen Z.
      • O’Shea J.J.
      Regulation of IL-17 production in human lymphocytes.
      ).
      Early studies had shown that in vitro polarization of human Th17 cells from naïve CD4+ cells occurs in the presence of toll-like receptor-activated monocytes (
      • Evans H.G.
      • Suddason T.
      • Jackson I.
      • Taams L.S.
      • Lord G.M.
      Optimal induction of T helper 17 cells in humans requires T cell receptor ligation in the context of Toll-like receptor-activated monocytes.
      ) and also that proinflammatory cytokines, such as IL-1β and IL-6, alone or in combination with IL-23, were able to drive Th17 differentiation (
      • Chen Z.
      • Tato C.M.
      • Muul L.
      • Laurence A.
      • O’Shea J.J.
      Distinct regulation of interleukin-17 in human T helper lymphocytes.
      ;
      • Wilson N.J.
      • Boniface K.
      • Chan J.R.
      • McKenzie B.S.
      • Blumenschein W.M.
      • Mattson J.D.
      • et al.
      Development, cytokine profile and function of human interleukin 17-producing helper T cells.
      ;
      • Acosta-Rodriguez E.V.
      • Napolitani G.
      • Lanzavecchia A.
      • Sallusto F.
      Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells.
      ). In particular, IL-1β was sufficient to induce the expression of RORC variant 2, the human ortholog of mouse RORγt, and the production of both IL-17A and IFN-γ (
      • Acosta-Rodriguez E.V.
      • Napolitani G.
      • Lanzavecchia A.
      • Sallusto F.
      Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells.
      ), whereas a combination of IL-6 and IL-1β promoted the differentiation of T cells producing IL-17A, but not IFN-γ (
      • Acosta-Rodriguez E.V.
      • Napolitani G.
      • Lanzavecchia A.
      • Sallusto F.
      Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells.
      ). Surface phenotype analysis of these cells showed that IL-17A-producing cells express the chemokine receptors, CCR6 and CCR4, whereas IFN-γ/IL-17-producing cells express CCR6 and CXCR3 (
      • Acosta-Rodriguez E.V.
      • Rivino L.
      • Geginat J.
      • Jarrossay D.
      • Gattorno M.
      • Lanzavecchia A.
      • et al.
      Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells.
      ). Recently, CD161 has been found to be expressed in IL-17A-producing cells and has been suggested as a novel surface marker for human Th17 cells (
      • Cosmi L.
      • De Palma R.
      • Santarlasci V.
      • Maggi L.
      • Capone M.
      • Frosali F.
      • et al.
      Human interleukin 17-producing cells originate from a CD161+CD4+ T cell precursor.
      ).
      However, the most challenging aspect of human Th17 biology is the role of TGFβ-1. Although dismissed for a while, an absolute need for TGFβ-1 in human Th17 differentiation is now being recognized (
      • O’Garra A.
      • Stockinger B.
      • Veldhoen M.
      Differentiation of human T(H)-17 cells does require TGF-beta!.
      ). Initial studies showed that TGFβ-1 does not promote Th17 differentiation but rather inhibits IL-17A production in a dose-dependent manner (
      • Chen Z.
      • Tato C.M.
      • Muul L.
      • Laurence A.
      • O’Shea J.J.
      Distinct regulation of interleukin-17 in human T helper lymphocytes.
      ;
      • Wilson N.J.
      • Boniface K.
      • Chan J.R.
      • McKenzie B.S.
      • Blumenschein W.M.
      • Mattson J.D.
      • et al.
      Development, cytokine profile and function of human interleukin 17-producing helper T cells.
      ;
      • Acosta-Rodriguez E.V.
      • Napolitani G.
      • Lanzavecchia A.
      • Sallusto F.
      Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells.
      ). However, recent reports have shown that in humans also, low concentrations of TGFβ-1 are necessary to differentiate human naïve CD4+ T cells into Th17 cells, either in combination with IL-21 (
      • Yang L.
      • Anderson D.E.
      • Baecher-Allan C.
      • Hastings W.D.
      • Bettelli E.
      • Oukka M.
      • et al.
      IL-21 and TGF-beta are required for differentiation of human T(H)17 cells.
      ), with IL-1β and IL-23 (
      • Manel N.
      • Unutmaz D.
      • Littman D.R.
      The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat.
      ) or with IL-1β, IL-23, and IL-6 (
      • Volpe E.
      • Servant N.
      • Zollinger R.
      • Bogiatzi S.I.
      • Hupe P.
      • Barillot E.
      • et al.
      A critical function for transforming growth factor-beta, interleukin 23 and proinflammatory cytokines in driving and modulating human T(H)-17 responses.
      ). Although these studies differ slightly in their conclusions about the relative role of proinflammatory mediators, they have collectively shown that, similar to that in mice (
      • Zhou L.
      • Lopes J.E.
      • Chong M.M.
      • Ivanov I.I.
      • Min R.
      • Victora G.D.
      • et al.
      TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function.
      ), TGF-β1 concentration and the concomitant presence of at least one proinflammatory cytokine are key factors in human Th17 differentiation. In fact, low concentrations of TGF-β1 synergizes with proinflammatory cytokines such as IL-1β, IL-6, IL-21, and IL-23 (
      • Manel N.
      • Unutmaz D.
      • Littman D.R.
      The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat.
      ;
      • Yang L.
      • Anderson D.E.
      • Baecher-Allan C.
      • Hastings W.D.
      • Bettelli E.
      • Oukka M.
      • et al.
      IL-21 and TGF-beta are required for differentiation of human T(H)17 cells.
      ) to promote IL-23R expression, thus favoring the differentiation of naïve cells into the Th17 effector lineage, whereas, high levels of TGF-β1 and the absence of inflammatory cytokines would rather inhibit Th17 differentiation, shifting the balance toward regulatory T cell development (
      • Manel N.
      • Unutmaz D.
      • Littman D.R.
      The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat.
      ). The presence of a discrete amount of TGF-β1 in the human and bovine serum used in earlier studies probably accounts for the inability to observe TGF-β-induced Th17 differentiation. Finally, using a different approach on the basis of particular genetic traits affecting putative Th17-relevant signals,
      • de Beaucoudrey L.
      • Puel A.
      • Filipe-Santos O.
      • Cobat A.
      • Ghandil P.
      • Chrabieh M.
      • et al.
      Mutations in STAT3 and IL12RB1 impair the development of human IL-17-producing T cells.
      have recently confirmed that, among other cytokines, IL-23 is indeed required for an optimal development of human Th17 cells.
      In parallel to factors required for Th17 commitment, natural inhibitors of Th17 development have also been identified. As mentioned, both Th1 (IFN-γ) and Th2 (IL-4) cytokines inhibit Th17 differentiation (
      • Harrington L.E.
      • Hatton R.D.
      • Mangan P.R.
      • Turner H.
      • Murphy T.L.
      • Murphy K.M.
      • et al.
      Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages.
      ;
      • Park H.
      • Li Z.
      • Yang X.O.
      • Chang S.H.
      • Nurieva R.
      • Wang Y.H.
      • et al.
      A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17.
      ). More recently, IL-25, a member of the IL-17 family earlier known as IL-17E and involved in Th2 response (
      • Angkasekwinai P.
      • Park H.
      • Wang Y.H.
      • Chang S.H.
      • Corry D.B.
      • Liu Y.J.
      • et al.
      Interleukin 25 promotes the initiation of proallergic type 2 responses.
      ), has been found to negatively regulate Th17 cells by inhibiting the expression of IL-1β and IL-23 by DC (
      • Kleinschek M.A.
      • Owyang A.M.
      • Joyce-Shaikh B.
      • Langrish C.L.
      • Chen Y.
      • Gorman D.M.
      • et al.
      IL-25 regulates Th17 function in autoimmune inflammation.
      ). Likewise, IL-27, belonging to the IL-6 family (
      • Pflanz S.
      • Timans J.C.
      • Cheung J.
      • Rosales R.
      • Kanzler H.
      • Gilbert J.
      • et al.
      IL-27, a heterodimeric cytokine composed of EBI3 and p28 protein, induces proliferation of naive CD4(+) T cells.
      ), also acts as a Th17 inhibitor, consistent with its capacity to drive a Th1 cell response (
      • Batten M.
      • Li J.
      • Yi S.
      • Kljavin N.M.
      • Danilenko D.M.
      • Lucas S.
      • et al.
      Interleukin 27 limits autoimmune encephalomyelitis by suppressing the development of interleukin 17-producing T cells.
      ;
      • Stumhofer J.S.
      • Laurence A.
      • Wilson E.H.
      • Huang E.
      • Tato C.M.
      • Johnson L.M.
      • et al.
      Interleukin 27 negatively regulates the development of interleukin 17-producing T helper cells during chronic inflammation of the central nervous system.
      ).
      In addition to IL-17A, Th17 cells have been collectively shown to also produce IL-17F, IL-22, and IL-26, as well as IL-6, IL-21, TNF-α, and IFN-γ (
      • Chen Z.
      • Tato C.M.
      • Muul L.
      • Laurence A.
      • O’Shea J.J.
      Distinct regulation of interleukin-17 in human T helper lymphocytes.
      ;
      • Wilson N.J.
      • Boniface K.
      • Chan J.R.
      • McKenzie B.S.
      • Blumenschein W.M.
      • Mattson J.D.
      • et al.
      Development, cytokine profile and function of human interleukin 17-producing helper T cells.
      ;
      • Acosta-Rodriguez E.V.
      • Napolitani G.
      • Lanzavecchia A.
      • Sallusto F.
      Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells.
      ;
      • Manel N.
      • Unutmaz D.
      • Littman D.R.
      The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat.
      ;
      • Volpe E.
      • Servant N.
      • Zollinger R.
      • Bogiatzi S.I.
      • Hupe P.
      • Barillot E.
      • et al.
      A critical function for transforming growth factor-beta, interleukin 23 and proinflammatory cytokines in driving and modulating human T(H)-17 responses.
      ). To date, IL-17A, IL-17F, and IL-26 are considered to be specific Th17 cytokines (
      • Manel N.
      • Unutmaz D.
      • Littman D.R.
      The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat.
      ), whereas the others, including IL-22, can be produced by Th1 cells also (
      • Volpe E.
      • Servant N.
      • Zollinger R.
      • Bogiatzi S.I.
      • Hupe P.
      • Barillot E.
      • et al.
      A critical function for transforming growth factor-beta, interleukin 23 and proinflammatory cytokines in driving and modulating human T(H)-17 responses.
      ). In this review, we will focus our attention on those cytokines produced by Th17 cells that have been shown to be of potential relevance to cutaneous inflammation.
      Human IL-17A is the founding member of the IL-17 cytokine family, which includes six members, IL-17A to F. Very little is known about IL-17B, IL-17C, and IL-17D, which are produced by non-T-cell sources, whereas IL-17E has been renamed IL-25 and IL-17F shares many features with IL-17A (
      • Weaver C.T.
      • Hatton R.D.
      • Mangan P.R.
      • Harrington L.E.
      IL-17 family cytokines and the expanding diversity of effector T cell lineages.
      ). Although Th17 cells are the major source of IL-17A, other IL-17A-producing cells have also been reported, including CD8+ cells (
      • Shin H.C.
      • Benbernou N.
      • Esnault S.
      • Guenounou M.
      Expression of IL-17 in human memory CD45RO+ T lymphocytes and its regulation by protein kinase A pathway.
      ), γδ-TCR cells (
      • Roark C.L.
      • Simonian P.L.
      • Fontenot A.P.
      • Born W.K.
      • O’Brien R.L.
      gammadelta T cells: an important source of IL-17.
      ), and natural killer T cells (
      • Rachitskaya A.V.
      • Hansen A.M.
      • Horai R.
      • Li Z.
      • Villasmil R.
      • Luger D.
      • et al.
      Cutting edge: NKT cells constitutively express IL-23 receptor and RORgammat and rapidly produce IL-17 upon receptor ligation in an IL-6-independent fashion.
      ). IL-17F shares 50% sequence homology with IL-17A and both cytokines can exist either as IL-17A and IL-17F homodimers or as IL-17A-IL-17F heterodimers (
      • Liang S.C.
      • Long A.J.
      • Bennett F.
      • Whitters M.J.
      • Karim R.
      • Collins M.
      • et al.
      An IL-17F/A heterodimer protein is produced by mouse Th17 cells and induces airway neutrophil recruitment.
      ). They all induce the expression of diverse proinflammatory cytokines (for example, IL-1β and IL-6), colony-stimulating factors (for example, GM-CSF and granulocyte colony-stimulating factors), and chemokines (for example, CXCL8, CXCL1, and CXCL10) from a variety of cells, including monocyte/macrophages, and epithelial cells. Accordingly, IL-17A and IL-17F have potent activity to mobilize, recruit, and activate neutrophils, thus linking adaptive and innate immunity (
      • Weaver C.T.
      • Hatton R.D.
      • Mangan P.R.
      • Harrington L.E.
      IL-17 family cytokines and the expanding diversity of effector T cell lineages.
      ).
      IL-22 is a member of the IL-10 cytokines family, and is mainly produced by T and natural killer cells (
      • Wolk K.
      • Kunz S.
      • Asadullah K.
      • Sabat R.
      Cutting edge: immune cells as sources and targets of the IL-10 family members?.
      ). Neither resting nor activated immune cells respond to IL-22. In contrast, tissue cells at outer body barriers, that is, of the skin, kidney, and the digestive and respiratory systems are targets of this cytokine. IL-22 functions by promoting antimicrobial defense mechanisms, protecting against tissue damage, and re-organizing non-immune tissues, such as epithelia, thus regulating terminal differentiation of KCs (
      • Wolk K.
      • Sabat R.
      Interleukin-22: a novel T- and NK-cell derived cytokine that regulates the biology of tissue cells.
      ).
      Functional analysis of Th17 cytokines has revealed an important and unique role for these cytokines in host protection against infections with extracellular pathogens. IL-17R-deficient mice are highly susceptible to infection by the Gram-negative bacterium, Klebsiella pneumoniae, and the fungus, Candida albicans (
      • Ye P.
      • Garvey P.B.
      • Zhang P.
      • Nelson S.
      • Bagby G.
      • Summer W.R.
      • et al.
      Interleukin-17 and lung host defense against Klebsiella pneumoniae infection.
      ;
      • Huang W.
      • Na L.
      • Fidel P.L.
      • Schwarzenberger P.
      Requirement of interleukin-17A for systemic anti-Candida albicans host defense in mice.
      ). In addition, the preferential production of IL-17 by T cells during infection by Bacteroides fragilis (
      • Chung D.R.
      • Kasper D.L.
      • Panzo R.J.
      • Chitnis T.
      • Grusby M.J.
      • Sayegh M.H.
      • et al.
      CD4+ T cells mediate abscess formation in intra-abdominal sepsis by an IL-17-dependent mechanism.
      ), Borrelia burgdorferi, Mycobacterium tuberculosis (
      • Infante-Duarte C.
      • Horton H.F.
      • Byrne M.C.
      • Kamradt T.
      Microbial lipopeptides induce the production of IL-17 in Th cells.
      ), and the fungal species (
      • LeibundGut-Landmann S.
      • Gross O.
      • Robinson M.J.
      • Osorio F.
      • Slack E.C.
      • Tsoni S.V.
      • et al.
      Syk- and CARD9-dependent coupling of innate immunity to the induction of T helper cells that produce interleukin 17.
      ), suggests that Th17 responses are triggered by specific pathogens and are required for their clearance. These data are supported by recent findings showing that null mutations in IL12B and IL12RB1 genes lead to impaired IL-17-producing T-cell development in patients with autosomal-recessive susceptibility to mycobacterial diseases (
      • de Beaucoudrey L.
      • Puel A.
      • Filipe-Santos O.
      • Cobat A.
      • Ghandil P.
      • Chrabieh M.
      • et al.
      Mutations in STAT3 and IL12RB1 impair the development of human IL-17-producing T cells.
      ). A number of autoimmune disorders have been associated with overproduction of Th17 cytokines, and interference with their production or action attenuate autoimmune diseases. IL-17-deficient mice are resistant to adjuvant-induced arthritis (
      • Nakae S.
      • Nambu A.
      • Sudo K.
      • Iwakura Y.
      Suppression of immune induction of collagen-induced arthritis in IL-17-deficient mice.
      ) and develop EAE with delayed onset and reduced severity (
      • Komiyama Y.
      • Nakae S.
      • Matsuki T.
      • Nambu A.
      • Ishigame H.
      • Kakuta S.
      • et al.
      IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis.
      ). Similarly, IL-17R antagonists (
      • Bush K.A.
      • Farmer K.M.
      • Walker J.S.
      • Kirkham B.W.
      Reduction of joint inflammation and bone erosion in rat adjuvant arthritis by treatment with interleukin-17 receptor IgG1 Fc fusion protein.
      ) and IL-17A-blocking antibodies (Abs) (
      • Hofstetter H.H.
      • Ibrahim S.M.
      • Koczan D.
      • Kruse N.
      • Weishaupt A.
      • Toyka K.V.
      • et al.
      Therapeutic efficacy of IL-17 neutralization in murine experimental autoimmune encephalomyelitis.
      ;
      • Langrish C.L.
      • Chen Y.
      • Blumenschein W.M.
      • Mattson J.
      • Basham B.
      • Sedgwick J.D.
      • et al.
      IL-23 drives a pathogenic T cell population that induces autoimmune inflammation.
      ) prevent the development of autoimmune diseases.
      Under homeostatic conditions, IL-17A is present in extremely low or undetectable concentrations in human sera but has been reported to be overproduced at the both serum and tissue level in inflammatory bowel diseases, MS, and RA; (
      • Kotake S.
      • Udagawa N.
      • Takahashi N.
      • Matsuzaki K.
      • Itoh K.
      • Ishiyama S.
      • et al.
      IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis.
      ;
      • Matusevicius D.
      • Kivisakk P.
      • He B.
      • Kostulas N.
      • Ozenci V.
      • Fredrikson S.
      • et al.
      Interleukin-17 mRNA expression in blood and CSF mononuclear cells is augmented in multiple sclerosis.
      ;
      • Lock C.
      • Hermans G.
      • Pedotti R.
      • Brendolan A.
      • Schadt E.
      • Garren H.
      • et al.
      Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis.
      ;
      • Fujino S.
      • Andoh A.
      • Bamba S.
      • Ogawa A.
      • Hata K.
      • Araki Y.
      • et al.
      Increased expression of interleukin 17 in inflammatory bowel disease.
      ). Similarly, IL-22-expressing T-cells are present in inflamed regions of the gut in patients with inflammatory bowel diseases but not in the normal colonic mucosa (
      • Andoh A.
      • Zhang Z.
      • Inatomi O.
      • Fujino S.
      • Deguchi Y.
      • Araki Y.
      • et al.
      Interleukin-22, a member of the IL-10 subfamily, induces inflammatory responses in colonic subepithelial myofibroblasts.
      ). IL-22 expression was also described in both synovial tissues and in mononuclear cells of the synovial fluid from RA patients (
      • Ikeuchi H.
      • Kuroiwa T.
      • Hiramatsu N.
      • Kaneko Y.
      • Hiromura K.
      • Ueki K.
      • et al.
      Expression of interleukin-22 in rheumatoid arthritis: potential role as a proinflammatory cytokine.
      ).

      Role Of Il-23 And Th17 Cells In Psoriasis

      IL-23 and the IL-23 receptor in psoriasis

      The role of IL-23 and IL-23R in cutaneous inflammation has been investigated both in mice and in humans. Intradermal injection of IL-23 in mice led to erythema, induration, and prominent dermal papillary blood vessels with histopathological features resembling psoriasis (
      • Chan J.R.
      • Blumenschein W.
      • Murphy E.
      • Diveu C.
      • Wiekowski M.
      • Abbondanzo S.
      • et al.
      IL-23 stimulates epidermal hyperplasia via TNF and IL-20R2-dependent mechanisms with implications for psoriasis pathogenesis.
      ). The morphological features of the IL-23-induced skin lesions were more severe than the ones induced by IL-12 (
      • Zheng Y.
      • Danilenko D.M.
      • Valdez P.
      • Kasman I.
      • Eastham-Anderson J.
      • Wu J.
      • et al.
      Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis.
      ). Furthermore, IL-23 was shown to mediate epidermal hyperplasia, acanthosis, hyperparakeratosis, and orthohyperkeratosis through TNF-α and IL-20R2 (
      • Chan J.R.
      • Blumenschein W.
      • Murphy E.
      • Diveu C.
      • Wiekowski M.
      • Abbondanzo S.
      • et al.
      IL-23 stimulates epidermal hyperplasia via TNF and IL-20R2-dependent mechanisms with implications for psoriasis pathogenesis.
      ). In a transgenic mouse model of skin inflammation overexpressing the common IL-12/IL-23 subunit, IL-12p40, under the influence of the keratin 14 promoter, it was shown that IL-12p40 and IL-23p19, but not IL-12p35, were constitutively produced by basal KCs (
      • Kopp T.
      • Lenz P.
      • Bello-Fernandez C.
      • Kastelein R.A.
      • Kupper T.S.
      • Stingl G.
      IL-23 production by cosecretion of endogenous p19 and transgenic p40 in keratin 14/p40 transgenic mice: evidence for enhanced cutaneous immunity.
      ). These data were complemented in humans by
      • Lee E.
      • Trepicchio W.L.
      • Oestreicher J.L.
      • Pittman D.
      • Wang F.
      • Chamian F.
      • et al.
      Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris.
      showing overexpression of IL-23p19 and IL-12p40, in the absence of IL-12p35, at the mRNA level in psoriatic skin lesions, when compared with that in uninvolved skin. IL-23p19 was mostly localized in the papillary dermis, and it was strongly expressed in monocytes, monocyte-derived DCs, and in mature DCs. Collectively, these data indicate that production of IL-23 occurs at inflammatory skin sites and is mediated by tissue-resident and/or recruited immune cells, such as DCs, and possibly KCs (
      • Piskin G.
      • Sylva-Steenland R.M.R.
      • Bos J.D.
      • Teunissen M.B.M.
      In vitro and in situ expression of IL-23 by keratinocytes in healthy skin and psoriasis lesions: enhanced expression in psoriatic skin.
      ).
      Little is known about the immediate downstream effects of IL-23 in psoriasis. IL-23 signals through the IL-23 receptor complex expressed on DCs, lymphocytes, natural killer T cells, and KCs. It has been recently shown that IL-23, in synergy with IL-1β, is able to enhance production of human-β-defensin-2, an antimicrobial peptide increased in psoriasis, in normal human KCs (
      • Kanda N.
      • Watanabe S.
      IL-12, IL-23, and IL-27 enhance human beta-defensin-2 production in human keratinocytes.
      ). Further evidence supporting a pathogenic role of IL-23 in psoriasis comes from the clinical data.
      • Zaba L.C.
      • Cardinale I.
      • Gilleaudeau P.
      • Sullivan-Whalen M.
      • Suarez Farinas M.
      • Fuentes-Duculan J.
      • et al.
      Amelioration of epidermal hyperplasia by TNF inhibition is associated with reduced Th17 responses.
      have shown that anti-TNF-α agents are able to modulate IL-23p19 and IL-12p40 mRNA levels, and the inflammatory infiltrate in the psoriatic skin. Furthermore, modulation of IL-23 by cyclosporin A, UV therapy, and by biological agents has been correlated to the clinical benefit in psoriatic patients (
      • Piskin G.
      • Tursen U.
      • Sylva-Steenland R.M.
      • Bos J.D.
      • Teunissen M.B.
      Clinical improvement in chronic plaque-type psoriasis lesions after narrow-band UVB therapy is accompanied by a decrease in the expression of IFN-gamma inducers – IL-12, IL-18 and IL-23.
      ;
      • Gottlieb A.B.
      • Chamian F.
      • Masud S.
      • Cardinale I.
      • Abello M.V.
      • Lowes M.A.
      • et al.
      TNF inhibition rapidly down-regulates multiple proinflammatory pathways in psoriasis plaques.
      ;
      • Lowes M.A.
      • Kikuchi T.
      • Fuentes-Duculan J.
      • Cardinale I.
      • Zaba L.C.
      • Haider A.S.
      • et al.
      Psoriasis vulgaris lesions contain discrete populations of Th1 and Th17 T cells.
      ;
      • Haider A.S.
      • Lowes M.A.
      • Suarez-Farinas M.
      • Zaba L.C.
      • Cardinale I.
      • Khatcherian A.
      • et al.
      Identification of cellular pathways of “type 1”, Th17 T cells, and TNF- and inducible nitric oxide synthase-producing dendritic cells in autoimmune inflammation through pharmacogenomic study of cyclosporine A in psoriasis.
      ).
      Finally, detailed genetic studies of the IL23R gene in psoriasis have recently shown that at least two non-synonymous single nucleotide polymorphisms, Arg381Gln and proline to leucine (Pro310Leu), independently contribute to a psoriasis phenotype (
      • Capon F.
      • Di Meglio P.
      • Szaub J.
      • Prescott N.J.
      • Dunster C.
      • Baumber L.
      • et al.
      Sequence variants in the genes for the interleukin-23 receptor (IL23R) and its ligand (IL12B) confer protection against psoriasis.
      ;
      • Cargill M.
      • Schrodi S.J.
      • Chang M.
      • Garcia V.E.
      • Brandon R.
      • Callis K.P.
      • et al.
      A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes.
      ;
      • Nair R.P.
      • Ruether A.
      • Stuart P.E.
      • Jenisch S.
      • Tejasvi T.
      • Hiremagalore R.
      • et al.
      Polymorphisms of the IL12B and IL23R genes are associated with psoriasis.
      ). These convincing genetic data, in combination with data showing an association between IL-12B and psoriasis, support the importance of the IL-23 (and possibly IL-12) pathway in psoriasis.

      Th17 cells and cytokines in psoriasis

      Consistent with the described role of Th17 cells in a variety of chronic inflammatory autoimmune-type diseases, there is a growing body of evidence supporting a major role of Th17 cells and Th17-related cytokines in psoriasis. The first observation that IL-17 could be a relevant cytokine in psoriasis was found in the late 1990s.
      • Teunissen M.B.
      • Koomen C.W.
      • de Waal Malefyt R.
      • Wierenga E.A.
      • Bos J.D.
      Interleukin-17 and interferon-gamma synergize in the enhancement of proinflammatory cytokine production by human keratinocytes.
      showed detectable levels of IL-17 mRNA in lesional psoriatic skin, but not in non-lesional skin, and showed that CD4+ and CD8+ clones derived from lesional psoriatic skin were able to produce IL-17 after stimulation with CD3/CD28 Abs. IL-17 was also shown to promote the production of IL-6, IL-8, GM-CSF, and ICAM-1 in KCs, synergizing with IFN-γ (
      • Albanesi C.
      • Scarponi C.
      • Cavani A.
      • Federici M.
      • Nasorri F.
      • Girolomoni G.
      Interleukin-17 is produced by both Th1 and Th2 lymphocytes, and modulates interferon-gamma- and interleukin-4-induced activation of human keratinocytes.
      ;
      • Koga C.
      • Kabashima K.
      • Shiraishi N.
      • Kobayashi M.
      • Tokura Y.
      Possible pathogenic role of Th17 cells for atopic dermatitis.
      ). IL-17-producing cells have been isolated from the dermis of psoriatic lesions (
      • Lowes M.A.
      • Kikuchi T.
      • Fuentes-Duculan J.
      • Cardinale I.
      • Zaba L.C.
      • Haider A.S.
      • et al.
      Psoriasis vulgaris lesions contain discrete populations of Th1 and Th17 T cells.
      ). Dermal localization of Th17 cells has also been documented in atopic dermatitis, with a higher percentage of IL-17-producing cells present in acute rather than in chronic lesions (
      • Koga C.
      • Kabashima K.
      • Shiraishi N.
      • Kobayashi M.
      • Tokura Y.
      Possible pathogenic role of Th17 cells for atopic dermatitis.
      ). Surface phenotypic analysis of IL-17-producing T cells derived from psoriatic skin as well as from intestinal biopsies of patients affected with CD, showed a predominantly CD161+ phenotype (
      • Cosmi L.
      • De Palma R.
      • Santarlasci V.
      • Maggi L.
      • Capone M.
      • Frosali F.
      • et al.
      Human interleukin 17-producing cells originate from a CD161+CD4+ T cell precursor.
      ). DCs isolated from psoriatic skin are able to increase the percentage of IL-17A production in allogenic T cells (
      • Zaba L.C.
      • Fuentes-Duculan J.
      • Eungdamrong N.J.
      • Abello M.V.
      • Novitskaya I.
      • Pierson K.C.
      • et al.
      Psoriasis is characterized by accumulation of immunostimulatory and Th1/Th17 cell-polarizing myeloid dendritic cells.
      ).
      Interestingly, in contrast to other potential Th17-type autoimmune diseases such as RA (
      • Chabaud M.
      • Durand J.M.
      • Buchs N.
      • Fossiez F.
      • Page G.
      • Frappart L.
      • et al.
      Human interleukin-17: a T cell-derived proinflammatory cytokine produced by the rheumatoid synovium.
      ; Kohno et al., 2008), CD (
      • Fujino S.
      • Andoh A.
      • Bamba S.
      • Ogawa A.
      • Hata K.
      • Araki Y.
      • et al.
      Increased expression of interleukin 17 in inflammatory bowel disease.
      ), MS (
      • Matusevicius D.
      • Kivisakk P.
      • He B.
      • Kostulas N.
      • Ozenci V.
      • Fredrikson S.
      • et al.
      Interleukin-17 mRNA expression in blood and CSF mononuclear cells is augmented in multiple sclerosis.
      ), systemic lupus erythematosus (
      • Wong C.K.
      • Ho C.Y.
      • Li E.K.
      • Lam C.W.
      Elevation of proinflammatory cytokine (IL-18, IL-17, IL-12) and Th2 cytokine (IL-4) concentrations in patients with systemic lupus erythematosus.
      ), and systemic sclerosis (
      • Kurasawa K.
      • Hirose K.
      • Sano H.
      • Endo H.
      • Shinkai H.
      • Nawata Y.
      • et al.
      Increased interleukin-17 production in patients with systemic sclerosis.
      ), no statistically significant differences in peripheral levels of IL-17A have been found in psoriatic patients when compared with that in controls (
      • Arican O.
      • Aral M.
      • Sasmaz S.
      • Ciragil P.
      Serum levels of TNF-alpha, IFN-gamma, IL-6, IL-8, IL-12, IL-17, and IL-18 in patients with active psoriasis and correlation with disease severity.
      ). This suggests that the major site of production of IL-17A in psoriasis may be the lesional skin infiltrated by Th17 cells. This concept is strengthened by the data derived from studies on cytokine profiles after various immunomodulatory treatments in RA and psoriatic patients. In RA, the efficacy of both cyclosporin A and anti-TNF-α therapies has been correlated to modulation of proinflammatory cytokines, both in peripheral blood and in synovia (
      • Cho M.L.
      • Ju J.H.
      • Kim K.W.
      • Moon Y.M.
      • Lee S.Y.
      • Min S.Y.
      • et al.
      Cyclosporine A inhibits IL-15-induced IL-17 production in CD4+ T cells via down-regulation of PI3K/Akt and NF-kappaB.
      ;
      • Kageyama Y.
      • Ichikawa T.
      • Nagafusa T.
      • Torikai E.
      • Shimazu M.
      • Nagano A.
      Etanercept reduces the serum levels of interleukin-23 and macrophage inflammatory protein-3 alpha in patients with rheumatoid arthritis.
      ). In contrast, in psoriasis, the use of cyclosporin A and anti-TNF-α agents has been reported to decrease cutaneous, but not peripheral, levels of proinflammatory cytokines, such as IFN-γ, IL-17A, IL-23p19, and CCL20 (
      • Zaba L.C.
      • Cardinale I.
      • Gilleaudeau P.
      • Sullivan-Whalen M.
      • Suarez Farinas M.
      • Fuentes-Duculan J.
      • et al.
      Amelioration of epidermal hyperplasia by TNF inhibition is associated with reduced Th17 responses.
      ;
      • Lowes M.A.
      • Kikuchi T.
      • Fuentes-Duculan J.
      • Cardinale I.
      • Zaba L.C.
      • Haider A.S.
      • et al.
      Psoriasis vulgaris lesions contain discrete populations of Th1 and Th17 T cells.
      ;
      • Haider A.S.
      • Cohen J.
      • Fei J.
      • Zaba L.C.
      • Cardinale I.
      • Toyoko K.
      • et al.
      Insights into gene modulation by therapeutic TNF and IFNgamma antibodies: TNF regulates IFNgamma production by T cells and TNF-regulated genes linked to psoriasis transcriptome.
      ).
      A key cytokine produced by Th17 cells is IL-22. The role of IL-22 in the pathogenesis of psoriasis has been extensively examined because of its peculiar activities in immune innate response and functions on epithelial cells (
      • Wolk K.
      • Witte E.
      • Wallace E.
      • Docke W.D.
      • Kunz S.
      • Asadullah K.
      • et al.
      IL-22 regulates the expression of genes responsible for antimicrobial defense, cellular differentiation, and mobility in keratinocytes: a potential role in psoriasis.
      ). IL-22, as well as IL-17, TNF-α, IL-1β, IL-6, IL-12p40, and IL-12, has been found elevated in ear tissues of a psoriasiform mouse model, that is, transgenic K14/VEGF mice treated with 12-O-tetradecanoyl phorbol-13-acetate (
      • Hvid H.
      • Teige I.
      • Kvist P.H.
      • Svensson L.
      • Kemp K.
      TPA induction leads to a Th17-like response in transgenic K14/VEGF mice: a novel in vivo screening model of psoriasis.
      ). IL-23 injection in rodents induces IL-22-dependent dermal inflammation, KC hyperproliferation, and epidermal acanthosis (
      • Wolk K.
      • Witte E.
      • Wallace E.
      • Docke W.D.
      • Kunz S.
      • Asadullah K.
      • et al.
      IL-22 regulates the expression of genes responsible for antimicrobial defense, cellular differentiation, and mobility in keratinocytes: a potential role in psoriasis.
      ;
      • Zheng Y.
      • Danilenko D.M.
      • Valdez P.
      • Kasman I.
      • Eastham-Anderson J.
      • Wu J.
      • et al.
      Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis.
      ). In a CD4 T-cell-dependent psoriasis mouse model, an IL-22-neutralizing Ab was able to modulate the cutaneous expression of S100A8, S100A9, defensin β1, and cathelicidins, as well as prevent the development of skin lesions (
      • Ma H.L.
      • Liang S.
      • Li J.
      • Napierata L.
      • Brown T.
      • Benoit S.
      • et al.
      IL-22 is required for Th17 cell-mediated pathology in a mouse model of psoriasis-like skin inflammation.
      ).
      In vitro studies have shown that IL-22 synergizes with IL-17A and IL-17F to enhance the KC expression of antimicrobial peptides (
      • Liang S.C.
      • Tan X.Y.
      • Luxenberg D.P.
      • Karim R.
      • Dunussi-Joannopoulos K.
      • Collins M.
      • et al.
      Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides.
      ;
      • Wilson N.J.
      • Boniface K.
      • Chan J.R.
      • McKenzie B.S.
      • Blumenschein W.M.
      • Mattson J.D.
      • et al.
      Development, cytokine profile and function of human interleukin 17-producing helper T cells.
      ). IL-22 can also drive epithelial cell release of chemokines, such as IL-8 (
      • Brand S.
      • Beigel F.
      • Olszak T.
      • Zitzmann K.
      • Eichhorst S.T.
      • Otte J.M.
      • et al.
      IL-22 is increased in active Crohn's disease and promotes proinflammatory gene expression and intestinal epithelial cell migration.
      ;
      • Liang S.C.
      • Tan X.Y.
      • Luxenberg D.P.
      • Karim R.
      • Dunussi-Joannopoulos K.
      • Collins M.
      • et al.
      Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides.
      ;
      • Koga C.
      • Kabashima K.
      • Shiraishi N.
      • Kobayashi M.
      • Tokura Y.
      Possible pathogenic role of Th17 cells for atopic dermatitis.
      ), a key factor for neutrophil recruitment into psoriatic lesions. Moreover, in reconstituted human epidermis, KCs express genes involved in tissue repair and wound healing responses on stimulation with IL-22 (
      • Sa S.M.
      • Valdez P.A.
      • Wu J.
      • Jung K.
      • Zhong F.
      • Hall L.
      • et al.
      The effects of IL-20 subfamily cytokines on reconstituted human epidermis suggest potential roles in cutaneous innate defense and pathogenic adaptive immunity in psoriasis.
      ).
      Finally, increased IL-22 mRNA and protein levels have been found both in the skin and blood of psoriatic patients (
      • Wolk K.
      • Witte E.
      • Wallace E.
      • Docke W.D.
      • Kunz S.
      • Asadullah K.
      • et al.
      IL-22 regulates the expression of genes responsible for antimicrobial defense, cellular differentiation, and mobility in keratinocytes: a potential role in psoriasis.
      ;
      • Boniface K.
      • Guignouard E.
      • Pedretti N.
      • Garcia M.
      • Delwail A.
      • Bernard F.X.
      • et al.
      A role for T cell-derived interleukin 22 in psoriatic skin inflammation.
      ). IL-22 mRNA levels were higher in lesional skin than in psoriatic peripheral monocytes (
      • Boniface K.
      • Guignouard E.
      • Pedretti N.
      • Garcia M.
      • Delwail A.
      • Bernard F.X.
      • et al.
      A role for T cell-derived interleukin 22 in psoriatic skin inflammation.
      ).
      From these data, a concept emerges that IL-17A and IL-22 are key mediators of cutaneous inflammation, linking Th17 pathology with epithelial pathology, thus contributing to the pathogenesis of psoriasis (Figure 3). The IL-23/Th17 axis model for psoriasis integrates the well-defined type-1 inflammatory pathway model, in which Th1, Tc1 (cytotoxic T cell type-1) lymphocytes, and DCs are the central orchestrators of the events leading to psoriasis (
      • Lew W.
      • Bowcock A.M.
      • Krueger J.G.
      Psoriasis vulgaris: cutaneous lymphoid tissue supports T-cell activation and “Type 1” inflammatory gene expression.
      ). The molecular spectrum of the type-1 model of psoriasis is dominated by IL-12, produced by DCs, TNF-α, and IFN-γ, released by Th1 and Tc1 lymphocytes, which act on KCs by increasing their proliferation rates and stimulating their ability to release proinflammatory mediators. Typically, in the psoriatic plaque, Th1 lymphocytes are localized in the dermis, whereas Tc1 lymphocytes are mainly found in the epidermis expressing α1β1 integrin (VLA-1, very late antigen-1), which binds to basement membrane collagen IV (
      • Conrad C.
      • Boyman O.
      • Tonel G.
      • Tun-Kyi A.
      • Laggner U.
      • de Fougerolles A.
      • et al.
      Alpha1beta1 integrin is crucial for accumulation of epidermal T cells and the development of psoriasis.
      ). Therefore, it can be postulated that, in the psoriatic plaque, dermal dendritic cells produce both IL-12 and IL-23, driving a mixed type-1/Th17 infiltrate that interacts with KCs, fibroblasts, endothelial cells, and neutrophils to create a psoriatic plaque.
      Figure thumbnail gr3
      Figure 3Th17 lymphocytes and psoriasis: cellular and molecular interactions with skin-resident cells. In the ‘IL-23/Th17 axis’ model for psoriasis, Th17 lymphocytes (Th17) interact with skin-resident cells, contributing to the psoriatic phenotype. In the dermis, IL-23, secreted by dermal dendritic cells (DDC), is able to induce Th17 lymphocyte activation with the consequent release of proinflammatory cytokines, such as IL-17A, IL-17F, IL-22, and IL-26. IL-17A, IL-17F, and IL-22 act on keratinocytes (KC) leading to epidermal hyperplasia, acanthosis, and hyperparakeratosis. Dermal CCR5+CXCR3+CXCR6+ Th1 and epidermal VLA-1+ Tc1 lymphocytes are activated by DDCs and produce TNF-α and IFN-γ, contributing to the pathogenesis of the disease. KC hyperproliferation might also be influenced by fibroblasts, which can release keratinocyte growth factor (KGF) through TNF-α stimulation. In the context of this proinflammatory milieu, activated KCs might produce IL-23, which could mediate a cross-talk with Th17 lymphocytes in synergy with IL-23 coming from DDC. Th17 cells induce KC to produce IL-8 and antimicrobial peptides (for example, S100A8, S100A9, and defensin β1/2) for recruitment of neutrophils, cathelicidin for activation of plasmacytoid dendritic cells (PDC), and vascular endothelial growth factor (VEGF) with resulting angiogenesis.

      Targeting the IL-23/Th17 pathway in the treatment of psoriasis

      Novel insights into the immunopathogenesis of psoriasis have led to the development of new effective therapies, characterized by highly selective mechanisms of action, targeting key immune cytokines and receptors.
      With regard to the IL-23/Th17 axis, targeting the common subunit, p40, of IL-12 and IL-23 has shown clinical benefits in autoimmune-type diseases, such as CD and psoriasis. Two anti-IL-12p40 monoclonal Abs have been developed, namely, CNTO-1275/ustekinumab and ABT-874. An oral IL-12/23 inhibitor has been tested in early clinical trials in CD (
      • Burakoff R.
      • Barish C.F.
      • Riff D.
      • Pruitt R.
      • Chey W.Y.
      • Farraye F.A.
      • et al.
      A phase 1/2A trial of STA 5326, an oral interleukin-12/23 inhibitor, in patients with active moderate to severe Crohn's disease.
      ).
      Both CNTO-1275 and ABT-874 are human IgG1 MAbs that bind to the p40 subunit of human IL-12 and IL-23, and prevent its interaction with IL-12Rβ1. Preclinical analyses in cynomolgus monkeys, in the monkey asthma model and in the marmoset model for MS, and in vitro studies have been conducted to evaluate the safety of anti-IL-12p40 (
      • Brok H.P.
      • van Meurs M.
      • Blezer E.
      • Schantz A.
      • Peritt D.
      • Treacy G.
      • et al.
      Prevention of experimental autoimmune encephalomyelitis in common marmosets using an anti-IL-12p40 monoclonal antibody.
      ;
      • t Hart B.A.
      • Brok H.P.
      • Remarque E.
      • Benson J.
      • Treacy G.
      • Amor S.
      • et al.
      Suppression of ongoing disease in a nonhuman primate model of multiple sclerosis by a human-anti-human IL-12p40 antibody.
      ). It has also been shown that anti-IL-12p40 can lead to a decrease in disease activity in the mouse models of MS (
      • Leonard J.P.
      • Waldburger K.E.
      • Schaub R.G.
      • Smith T.
      • Hewson A.K.
      • Cuzner M.L.
      • et al.
      Regulation of the inflammatory response in animal models of multiple sclerosis by interleukin-12.
      ) and CD (
      • Neurath M.F.
      • Fuss I.
      • Kelsall B.L.
      • Stuber E.
      • Strober W.
      Antibodies to interleukin 12 abrogate established experimental colitis in mice.
      ). Anti-IL-12p40 successfully abolished psoriatic lesions in mice, even when administered after transfer of the T-cell subset that induced the psoriasis-like condition (
      • Hong K.
      • Chu A.
      • Lùdvìksson B.R.
      • Berg E.L.
      • Ehrhardt R.O.
      IL-12, independently of IFN-gamma, plays a crucial role in the pathogenesis of a murine psoriasis-like skin disorder.
      ;
      • Ma H.L.
      • Liang S.
      • Li J.
      • Napierata L.
      • Brown T.
      • Benoit S.
      • et al.
      IL-22 is required for Th17 cell-mediated pathology in a mouse model of psoriasis-like skin inflammation.
      ).
      In humans, results from phase I (
      • Kauffman C.L.
      • Aria N.
      • Toichi E.
      • McCormick T.E.
      • Cooper K.D.
      • Gottlieb A.B.
      • et al.
      A phase I study evaluating the safety, pharmacokinetics, and clinical response of a human IL-12 p40 antibody in subjects with plaque psoriasis.
      ) and phase II studies (
      • Krueger G.G.
      • Langley R.G.
      • Leonardi C.
      • Yeilding N.
      • Guzzo C.
      • Wang Y.
      • CNTO 1275 Psoriasis Study Group
      A human interleukin-12/23 monoclonal antibody for the treatment of plaque psoriasis.
      ;
      • Kimball A.B.
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      • Menter A.
      • Chartash E.K.
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      Safety and efficacy of ABT-874, a fully human interleukin 12/23 monoclonal antibody, in the treatment of moderate to severe chronic plaque psoriasis: results of a randomized, placebo-controlled, phase 2 trial.
      ) have shown that both CNTO-1275 and ABT-874 can be appropriate treatments for moderate-to-severe psoriasis (
      • Nestle F.O.
      • Conrad C.
      The IL-12 family member p40 chain as a master switch and novel therapeutic target in psoriasis.
      ), being able to modulate IL-8, IL-18, IFN-γ, cutaneous lymphocyte antigens (CLA), IL-12R, CD40L, and IL-2Rα expressions and to inhibit the secretion of cytokines induced by IL-12, and IL-23 in psoriasis as well as in CD (
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      • Hornung R.L.
      • Heller F.
      • et al.
      Both IL-12p70 and IL-23 are synthesized during active Crohn's disease and are down-regulated by treatment with anti-IL-12 p40 monoclonal antibody.
      ;
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      • McCormick T.S.
      • Chang T.
      • Mascelli M.A.
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      • et al.
      An anti-IL-12p40 antibody down-regulates type 1 cytokines, chemokines, and IL-12/IL-23 in psoriasis.
      ;
      • Gottlieb A.B.
      • Cooper K.D.
      • McCormick T.S.
      • Toichi E.
      • Everitt D.E.
      • Frederick B.
      • et al.
      A phase 1, double-blind, placebo-controlled study evaluating single subcutaneous administrations of a human interleukin-12/23 monoclonal antibody in subjects with plaque psoriasis.
      ;
      • Reddy M.
      • Davis C.
      • Wong J.
      • Marsters P.
      • Pendley C.
      • Prabhakar U.
      Modulation of CLA, IL-12R, CD40L, and IL-2Ra expression and inhibition of IL-12- and IL-23-induced cytokine secretion by CNTO 1275.
      ). Indeed, clinical data from phase II studies on anti-IL-12p40 in CD further support IL-12p40 as an appropriate target for CD therapy (
      • Mannon P.J.
      • Fuss I.J.
      • Mayer L.
      • Elson C.O.
      • Sandborn W.J.
      • Present D.
      • et al.
      Anti-interleukin-12 antibody for active Crohn's disease.
      ). Notably, an oral treatment, STA-5326, which acts as a selective transcription inhibitor with potent anti-IL-12 and anti-IL-23 activity, has been reported as effective in preclinical studies on rat and murine models of CD and in a phase I/IIA trial in active moderate-to-severe CD (
      • Burakoff R.
      • Barish C.F.
      • Riff D.
      • Pruitt R.
      • Chey W.Y.
      • Farraye F.A.
      • et al.
      A phase 1/2A trial of STA 5326, an oral interleukin-12/23 inhibitor, in patients with active moderate to severe Crohn's disease.
      ;
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      • Lu R.
      • Zhou D.
      • Chu J.
      • Przewloka T.
      • Zhang S.
      • et al.
      Selective abrogation of Th1 response by STA-5326, a potent IL-12/IL-23 inhibitor.
      ).
      Currently, several phase III trials have been published or are ongoing to evaluate the efficacy and safety of the anti-IL-12p40 MAb versus placebo or etanercept (anti-TNF-α therapy) in the treatment of moderate-to-severe chronic plaque psoriasis.
      Leonardi et al. and Papp et al. have published the results of the PHOENIX 1 (
      • Leonardi C.L.
      • Kimball A.B.
      • Papp K.A.
      • Yeilding N.
      • Guzzo C.
      • Wang Y.
      • et al.
      Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1).
      ) and PHOENIX 2 (
      • Papp K.A.
      • Langley R.G.
      • Lebwohl M.
      • Krueger G.G.
      • Szapary P.
      • Yeilding N.
      • et al.
      Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2).
      ), phase III, randomized, placebo-controlled trials evaluating the efficacy and safety of ustekinumab in moderate-to-severe psoriasis.
      The PHOENIX 1 trial assessed the efficacy and safety of ustekinumab 45 and 90mg, administered subcutaneously at weeks 0, 4, and then every 12 weeks over 76 weeks of treatment. Overall, a larger number of patients in the ustekinumab arm (both 45 and 90mg) achieved PASI (Psoriasis Area and Severity Index)-75 at week 12 when compared with those in placebo (PASI-75 response in 67.1, 66.4, and 3.1%, respectively). Efficacy increased over time with the maximum effect at week 24 (PASI-75 response observed in 76.1% of patients treated with 45mg and in 85% of patients in the 90mg group) and improvement in the PASI score remained stable up to at least week 76. The occurrence of adverse events was similar during the whole duration of the study; it was not statistically different from the placebo group, and did not require treatment adjustment. The most commonly reported adverse events were mild and considered non-serious, and mostly consisted of upper respiratory tract infections, nasopharyngitis, headache, and arthralgia.
      The aim of the PHOENIX 2 trial was to assess whether dosing intensification would increase the response to treatment in partial responder patients (between PASI-50 and PASI-75). The results up to week 28 were comparable with the ones reported in PHOENIX 1. At week 28, patients who responded to ustekinumab continued to receive the study agent every 12 weeks and maintained a good response up to week 52. Partial responders at week 28 (22.7 and 15.8% of patients in the 45 and 90mg group, respectively) were randomly assigned to continue treatment every 12 weeks or, through an intensified regimen, every 8 weeks. Dosing intensification did result in increased clinical efficacy only in patients receiving 90mg, and not 45mg, of ustekinumab every 8 weeks (PASI-75 in 68.8% of patients receiving 90mg every 8 weeks versus 33.3% of patients receiving 90mg every 12 weeks). The incidence and the kind of adverse events that occurred during the PHOENIX 2 study did not differ from those reported in the PHOENIX 1 trial.
      Overall, the results of the clinical studies on the efficacy of anti-IL-12p40 Abs observed so far are promising, suggesting that ustekinumab and possibly ABT-874 could provide a new and effective treatment for moderate-to-severe psoriasis, thus stressing the important role of IL-12/IL-23 in the pathogenesis of the disease. Moreover, anti-IL-12p40 Abs have so far shown a good safety profile during treatment periods of up to 76 weeks. Nevertheless, long-term safety issues are to be considered given the relevant part played by IL-12p40 in host defense (
      • Trinchieri G.
      Proinflammatory and immunoregulatory functions of interleukin-12.
      ), potentially leading to increased susceptibility to infections in patients treated with anti-IL-12p40. In humans, mutations in the IL-12p40 subunit or in its receptor have been associated with susceptibility to tuberculosis and salmonella infections, but not to viral or fungal infections (
      • Altare F.
      • Durandy A.
      • Lammas D.
      • Emile J.F.
      • Lamhamedi S.
      • Le Deist F.
      • et al.
      Impairment of mycobacterial immunity in human interleukin-12 receptor deficiency.
      ;
      • de Jong R.
      • Altare F.
      • Haagen I.A.
      • Elferink D.G.
      • Boer T.
      • van Breda Vriesman P.J.
      • et al.
      Severe mycobacterial and Salmonella infections in interleukin-12 receptor-deficient patients.
      ;
      • Oxenius A.
      • Karrer U.
      • Zinkernagel R.M.
      • Hengartner H.
      IL-12 is not required for induction of type 1 cytokine responses in viral infections.
      ).
      Taken together, targeting both IL-12 and IL-23 is a highly effective therapeutic approach in chronic plaque-type psoriasis. Future studies will show if targeting IL-23 on its own will be effective. Longer follow-up periods with the establishment of treatment registries are necessary to confirm the safety of anti-IL-12p40 Abs in the treatment of moderate-to-severe chronic plaque psoriasis.

      Conclusions

      A significant amount of both clinical and experimental data have established Th17 cells as key players in chronic inflammatory conditions, such as psoriasis, providing an exciting advance in our understanding of psoriasis immunopathogenesis and novel therapeutic targets.
      This puts the spotlight on IL-23, which is secreted by skin DCs, and induces production of proinflammatory mediators by Th17 cells such as IL-17A, IL-17F, and IL-22. These mediators will act on KCs leading to their activation and hyperproliferation. In the cross-talk between KC and Th17 cells, activated KCs produce key proinflammatory cytokines, chemokines, and antimicrobial peptides, which are able to recruit and activate immune cells in the inflamed skin. These events result in amplification of the immune response, leading to the clinical features of the disease.
      Integration of the IL-23/Th17 axis into a revised concept of psoriasis pathogenesis has been already translated into novel therapeutic strategies, which are proving to be effective and safe in the treatment of chronic plaque psoriasis. Future investigations will further clarify the role of key components of the IL-23/Th17 axis, and their interplay with other relevant cellular and molecular pathways of the innate and adaptive immune system in psoriasis.

      Conflict of Interest

      Dr Nestle has provided consultant activity to Centocor, Abbott, and Janssen Cilag. The other authors state no conflict of interest.

      ACKNOWLEDGMENTS

      We acknowledge the support by the following grant funding bodies: Wellcome Trust, NIH, NIHR Comprehensive Biomedical Research Centre Guy's and St Thomas’ Hospital and King's College London, Medical Research Council UK, SIDeMaST fellowship award, Dunhill Medical Trust.

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