IL-6 signaling in psoriasis prevents immune suppression by regulatory T cells.
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-6Ralpha and gp130 expression was significantly elevated in psoriatic effector T cells compared with normal controls. Overall, IL-6Ralpha 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.
Goodman
Wendy A
WA
Department of Dermatology, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, OH 44106-4952, USA. wag@case.edu
Levine
Alan D
AD
Massari
Jessica V
JV
Sugiyama
Hideaki
H
McCormick
Thomas S
TS
Cooper
Kevin D
KD
D000328:Adult; D002465:Cell Movement / Q000276:immunology; D002478:Cells, Cultured; D020405:Dermis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007165:Immunosuppression Therapy; D015850:Interleukin-6 / Q000378:metabolism / Q000502:physiology*; D011565:Psoriasis / Q000276:immunology* / Q000473:pathology*; D015398:Signal Transduction / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology
C508600:IL6 protein, human; D015850:Interleukin-6