IL-6 Signaling in Psoriasis Prevents Immune Suppression by Regulatory T Cells1

T memory/effector cells (Tmem/eff) isolated from psoriatic patients are chronically activated and poorly suppressed by regulatory T cells (Treg). The proinflammatory cytokine IL-6, which signals through Stat3, allows escape of Tmem/eff cells from Treg-mediated suppression in a murine system. We show here that IL-6 protein is markedly elevated and most highly expressed by CD31+ endothelial cells and CD11c+ dermal dendritic cells (DCs) in lesional psoriatic skin. We hypothesized that exposure to high IL-6 in lesional tissue may lead to the dampened Treg function observed in psoriasis patients. Indeed, we found that IL-6, but not other Stat3-activating cytokines, was necessary and sufficient to reverse human T cell suppression by Treg in an in vitro model using activated DCs as a source of IL-6. IL-6Rα and gp130 expression was significantly elevated in psoriatic effector T cells compared with normal controls. Overall, IL-6Rα expression on Treg exceeded that of effector T cells, and both populations phosphorylated Stat3 in response to IL-6. Phosphorylation of Stat3 in T cells contributes to Th17 differentiation and we identify cells within lesional tissue that coexpress CD3, IL-17, and IL-6, indicating that Th17 cells are present in vivo within the psoriatic Tmem/eff population and contribute to IL-6-mediated resistance to Treg suppression. Taken together, T lymphocytes trafficking into lesional psoriatic skin encounter high IL-6 from endothelial cells, DCs, and Th17 cells, enabling cutaneous T cell escape from Treg suppression and Th17 participation in inflammation. Targeting IL-6 signaling pathways in psoriasis may rebalance Treg/T effector activity and ameliorate disease.

[1]  J. Ward,et al.  Th1, Th2, and Th17 Effector T Cell-Induced Autoimmune Gastritis Differs in Pathological Pattern and in Susceptibility to Suppression by Regulatory T Cells1 , 2008, The Journal of Immunology.

[2]  David E. Anderson,et al.  IL-21 and TGF-β are required for differentiation of human TH17 cells , 2008, Nature.

[3]  T. Ohkawara,et al.  IL-6 blockade inhibits the induction of myelin antigen-specific Th17 cells and Th1 cells in experimental autoimmune encephalomyelitis , 2008, Proceedings of the National Academy of Sciences.

[4]  D. Riethmacher,et al.  In vivo equilibrium of proinflammatory IL-17+ and regulatory IL-10+ Foxp3+ RORγt+ T cells , 2008, The Journal of experimental medicine.

[5]  Lisa C. Zaba,et al.  Psoriasis vulgaris lesions contain discrete populations of Th1 and Th17 T cells. , 2008, The Journal of investigative dermatology.

[6]  A. Levine,et al.  TGF-β Inhibits IL-2 Production and Promotes Cell Cycle Arrest in TCR-Activated Effector/Memory T Cells in the Presence of Sustained TCR Signal Transduction1 , 2008, The Journal of Immunology.

[7]  J. O’Shea,et al.  Th17 cells: a new fate for differentiating helper T cells , 2008, Immunologic research.

[8]  Lisa C. Zaba,et al.  Amelioration of epidermal hyperplasia by TNF inhibition is associated with reduced Th17 responses , 2007, The Journal of experimental medicine.

[9]  T. McCormick,et al.  Cytokines and psoriasis: When cytokines become "pathokines" , 2007 .

[10]  D. Levy,et al.  IL-6 programs TH-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways , 2007, Nature Immunology.

[11]  T. Naka,et al.  IL-6-dependent and -independent pathways in the development of interleukin 17-producing T helper cells , 2007, Proceedings of the National Academy of Sciences.

[12]  B. Nickoloff.  Cracking the cytokine code in psoriasis , 2007, Nature Medicine.

[13]  T. Macdonald,et al.  IL-21 Counteracts the Regulatory T Cell-Mediated Suppression of Human CD4+ T Lymphocytes1 , 2007, The Journal of Immunology.

[14]  A. Gottlieb,et al.  An Anti-IL-12p40 Antibody Down-Regulates Type 1 Cytokines, Chemokines, and IL-12/IL-23 in Psoriasis1 , 2006, The Journal of Immunology.

[15]  Shimon Sakaguchi,et al.  Foxp3+CD25+CD4+ natural regulatory T cells in dominant self‐tolerance and autoimmune disease , 2006, Immunological reviews.

[16]  J. Scheller,et al.  Interleukin-6 and its receptor: from bench to bedside , 2006, Medical Microbiology and Immunology.

[17]  M. Wasik,et al.  STAT3- and DNA methyltransferase 1-mediated epigenetic silencing of SHP-1 tyrosine phosphatase tumor suppressor gene in malignant T lymphocytes. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[18]  D. Levy,et al.  Novel roles of unphosphorylated STAT3 in oncogenesis and transcriptional regulation. , 2005, Cancer research.

[19]  T. Mcclanahan,et al.  IL-23 drives a pathogenic T cell population that induces autoimmune inflammation , 2005, The Journal of experimental medicine.

[20]  S. Stevens,et al.  Dysfunctional Blood and Target Tissue CD4+CD25high Regulatory T Cells in Psoriasis: Mechanism Underlying Unrestrained Pathogenic Effector T Cell Proliferation1 , 2005, The Journal of Immunology.

[21]  E. Shevach,et al.  Naturally-occurring CD4+CD25+ immunoregulatory T cells: central players in the arena of peripheral tolerance. , 2004, Seminars in immunology.

[22]  P. Heinrich,et al.  Principles of interleukin (IL)-6-type cytokine signalling and its regulation. , 2003, The Biochemical journal.

[23]  Ruslan Medzhitov,et al.  Toll Pathway-Dependent Blockade of CD4+CD25+ T Cell-Mediated Suppression by Dendritic Cells , 2003, Science.

[24]  T. Mcclanahan,et al.  A Receptor for the Heterodimeric Cytokine IL-23 Is Composed of IL-12Rβ1 and a Novel Cytokine Receptor Subunit, IL-23R1 , 2002, The Journal of Immunology.

[25]  G. Freeman,et al.  CD4+CD25high Regulatory Cells in Human Peripheral Blood1 , 2001, The Journal of Immunology.

[26]  G. Krueger,et al.  Treatment of chronic plaque psoriasis by selective targeting of memory effector T lymphocytes. , 2001, The New England journal of medicine.

[27]  J. Szepietowski,et al.  Increased interleukin‐7 levels in the sera of psoriatic patients: lack of correlations with interleukin‐6 levels and disease intensity , 2000, Clinical and experimental dermatology.

[28]  L. Culp,et al.  Overexpression of the oncofetal Fn variant containing the EDA splice-in segment in the dermal-epidermal junction of psoriatic uninvolved skin. , 2000, The Journal of investigative dermatology.

[29]  S. K. Szabo,et al.  Identification and quantitation of interferon-gamma producing T cells in psoriatic lesions: localization to both CD4+ and CD8+ subsets. , 1998, The Journal of investigative dermatology.

[30]  J. Voorhees,et al.  Fibronectin and alpha5 integrin regulate keratinocyte cell cycling. A mechanism for increased fibronectin potentiation of T cell lymphokine-driven keratinocyte hyperproliferation in psoriasis. , 1998, The Journal of clinical investigation.

[31]  James G. Krueger,et al.  Response of psoriasis to a lymphocyte-selective toxin (DAB389IL-2) suggests a primary immune, but not keratinocyte, pathogenic basis , 1995, Nature Genetics.

[32]  F. Trautinger,et al.  Increased IL-6 production by monocytes and keratinocytes in patients with psoriasis. , 1991, The Journal of investigative dermatology.

[33]  J. Voorhees,et al.  Proliferating cells in psoriatic dermis are comprised primarily of T cells, endothelial cells, and factor XIIIa+ perivascular dendritic cells. , 1991, The Journal of investigative dermatology.

[34]  T. Annesley,et al.  Cyclosporine for plaque-type psoriasis. Results of a multidose, double-blind trial. , 1991, The New England journal of medicine.

[35]  J. Voorhees,et al.  Mechanisms of cyclosporine A inhibition of antigen-presenting activity in uninvolved and lesional psoriatic epidermis. , 1990, The Journal of investigative dermatology.

[36]  D. P. Murphy,et al.  Interleukin 6 is expressed in high levels in psoriatic skin and stimulates proliferation of cultured human keratinocytes. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[37]  David E. Anderson,et al.  OR.41. IL-21 and TGF-β are Required for Differentiation of Human Th17 Cells , 2008 .

[38]  J. Clifford,et al.  Stat3 links activated keratinocytes and immunocytes required for development of psoriasis in a novel transgenic mouse model , 2005, Nature Medicine.

[39]  J. Voorhees,et al.  Kinetics and regulation of human keratinocyte stem cell growth in short-term primary ex vivo culture. Cooperative growth factors from psoriatic lesional T lymphocytes stimulate proliferation among psoriatic uninvolved, but not normal, stem keratinocytes. , 1995, The Journal of clinical investigation.