{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T20:56:31Z","timestamp":1793048191239,"version":"4.5.0"},"reference-count":38,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2009,9,1]],"date-time":"2009-09-01T00:00:00Z","timestamp":1251763200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2009,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>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-6R\u03b1 and gp130 expression was significantly elevated in psoriatic effector T cells compared with normal controls. Overall, IL-6R\u03b1 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.<\/jats:p>","DOI":"10.4049\/jimmunol.0803721","type":"journal-article","created":{"date-parts":[[2009,7,31]],"date-time":"2009-07-31T21:10:19Z","timestamp":1249074619000},"page":"3170-3176","source":"Crossref","is-referenced-by-count":285,"title":["IL-6 Signaling in Psoriasis Prevents Immune Suppression by Regulatory T Cells"],"prefix":"10.1093","volume":"183","author":[{"given":"Wendy A","family":"Goodman","sequence":"first","affiliation":[{"name":"Department of Dermatology"},{"name":"Department of Pathology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan D","family":"Levine","sequence":"additional","affiliation":[{"name":"Department of Pathology"},{"name":"Department of Medicine, Case Western Reserve University and University Hospitals Case Medical Center , Cleveland, OH 44106"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica V","family":"Massari","sequence":"additional","affiliation":[{"name":"Department of Dermatology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideaki","family":"Sugiyama","sequence":"additional","affiliation":[{"name":"Department of Dermatology"},{"name":"Department of Dermatology, University of Yamanashi , Chuo,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas S","family":"McCormick","sequence":"additional","affiliation":[{"name":"Department of Dermatology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin D","family":"Cooper","sequence":"additional","affiliation":[{"name":"Department of Dermatology"},{"name":"Department of Pathology"},{"name":"Department of Dermatology, Louis Stokes Cleveland Veterans Affairs Medical Center , Cleveland, OH 44106"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2009,9,1]]},"reference":[{"key":"2026012811243516300_R1","first-page":"1509","article-title":"Fibronectin and \u03b15 integrin regulate keratinocyte cell cycling: a mechanism for increased fibronectin potentiation of T cell lymphokine-driven keratinocyte hyperproliferation in psoriasis.","volume-title":"J. Clin. Invest.","year":"1998"},{"key":"2026012811243516300_R2","first-page":"649","article-title":"Mechanisms of cyclosporine A inhibition of antigen-presenting activity in uninvolved and lesional psoriatic epidermis.","volume-title":"J. Invest. Dermatol.","year":"1990"},{"key":"2026012811243516300_R3","first-page":"333","article-title":"Proliferating cells in psoriatic dermis are comprised primarily of T cells, endothelial cells, and factor XIIIa+ perivascular dendritic cells.","volume-title":"J. Invest. Dermatol.","year":"1991"},{"key":"2026012811243516300_R4","first-page":"277","article-title":"Cyclosporine for plaque-type psoriasis: results of a multidose, double-blind trial.","volume-title":"N. Engl. J. Med.","year":"1991"},{"key":"2026012811243516300_R5","first-page":"4917","article-title":"An anti-IL-12p40 antibody down-regulates type 1 cytokines, chemokines, and IL-12\/IL-23 in psoriasis.","volume-title":"J. Immunol.","year":"2006"},{"key":"2026012811243516300_R6","first-page":"248","article-title":"Treatment of chronic plaque psoriasis by selective targeting of memory effector T lymphocytes.","volume-title":"N. Engl. J. Med.","year":"2001"},{"key":"2026012811243516300_R7","first-page":"442","article-title":"Response of psoriasis to a lymphocyte-selective toxin (DAB389IL-2) suggests a primary immune, but not keratinocyte, pathogenic basis.","volume-title":"Nat. Med.","year":"1995"},{"key":"2026012811243516300_R8","first-page":"81","article-title":"Naturally-occurring CD4+CD25+ immunoregulatory T cells: central players in the arena of peripheral tolerance.","volume-title":"Semin. Immunol.","year":"2004"},{"key":"2026012811243516300_R9","first-page":"8","article-title":"Foxp3+CD25+CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease.","volume-title":"Immunol. 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Invest.","year":"1995"},{"key":"2026012811243516300_R14","first-page":"706","article-title":"Overexpression of the oncofetal Fn variant containing the EDA splice-in segment in the dermal-epidermal junction of psoriatic uninvolved skin.","volume-title":"J. Invest. Dermatol.","year":"2000"},{"key":"2026012811243516300_R15","first-page":"1033","article-title":"Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells.","volume-title":"Science","year":"2003"},{"key":"2026012811243516300_R16","first-page":"6367","article-title":"Interleukin 6 is expressed in high levels in psoriatic skin and stimulates proliferation of cultured human keratinocytes.","volume-title":"Proc. Natl. Acad. Sci. USA","year":"1989"},{"key":"2026012811243516300_R17","first-page":"27","article-title":"Increased IL-6 production by monocytes and keratinocytes in patients with psoriasis.","volume-title":"J. Invest. Dermatol.","year":"1991"},{"key":"2026012811243516300_R18","first-page":"1072","article-title":"Identification and quantitation of interferon-\u03b3 producing T cells in psoriatic lesions: localization to both CD4+ and CD8+ subsets.","volume-title":"J. Invest. Dermatol.","year":"1998"},{"key":"2026012811243516300_R19","first-page":"1245","article-title":"CD4+CD25high regulatory cells in human peripheral blood.","volume-title":"J. Immunol.","year":"2001"},{"key":"2026012811243516300_R20","first-page":"1490","article-title":"TGF-\u03b2 inhibits IL-2 production and promotes cell cycle arrest in TCR-activated effector\/memory T cells in the presence of sustained TCR signal transduction.","volume-title":"J. Immunol.","year":"2008"},{"key":"2026012811243516300_R21","first-page":"233","article-title":"IL-23 drives a pathogenic T cell population that induces autoimmune inflammation.","volume-title":"J. Exp. 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