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* Department of Dermatology,
Department of Pathology, and
Department of Medicine, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, OH 44106;
Department of Dermatology, University of Yamanashi, Chuo, Japan; and
¶ Department of Dermatology, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH 44106
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
and gp130 expression was significantly elevated in psoriatic effector T cells compared with normal controls. Overall, IL-6R 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was funded by National Institutes of Health Grants AR-051498, P30AR39750, and P50AR05508 (to K.D.C.), the Morphology, Flow Cytometry, and Confocal Microscopy core facilities of the National Institute of Arthritis and Musculoskeletal and Skin Diseases Research Center and the Case Comprehensive Cancer Center (Grant P30CA43703), and the Murdough Family Center for Psoriasis.
2 Address correspondence and reprint requests to Dr. Wendy A. Goodman, Department of Dermatology, University Hospitals Case Medical Center and Case Western Reserve University, 10900 Euclid Avenue, BRB 409A, Cleveland, OH, 44106-4952. E-mail address: wag{at}case.edu
3 Abbreviations used in this paper: Tmem/eff, T memory effector cell; Treg, regulatory T cell; DC, dendritic cell; rh, recombinant human; sIL-6R, soluble IL-6R; MFI, mean fluorescence intensity; DCCM, DC-conditioned medium.
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