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Induction of interleukin‐10 in the T helper type 17 effector population by the G protein coupled estrogen receptor (GPER) agonist G‐1
Author(s) -
Brunsing Ryan L.,
Prossnitz Eric R.
Publication year - 2011
Publication title -
immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.297
H-Index - 133
eISSN - 1365-2567
pISSN - 0019-2805
DOI - 10.1111/j.1365-2567.2011.03471.x
Subject(s) - biology , cytotoxic t cell , t cell , zap70 , foxp3 , interleukin 21 , rar related orphan receptor gamma , il 2 receptor , population , microbiology and biotechnology , immune system , endocrinology , immunology , medicine , in vitro , biochemistry , environmental health
Summary Interleukin‐10 (IL‐10) is a potent suppressor of the immune system, commonly produced by CD4 + T cells to limit ongoing inflammatory responses minimizing host damage. Many autoimmune diseases are marked by large populations of activated CD4 + T cells within the setting of chronic inflammation; therefore, drugs capable of inducing IL‐10 production in CD4 + T cells would be of great therapeutic value. Previous reports have shown that the small molecule G‐1, an agonist of the membrane‐bound G‐protein‐coupled estrogen receptor GPER, attenuates disease in an animal model of autoimmune encephalomyelitis. However, the direct effects of G‐1 on CD4 + T‐cell populations remain unknown. Using ex vivo cultures of purified CD4 + T cells, we show that G‐1 elicits IL‐10 expression in T helper type 17 (Th17) ‐polarized cells, increasing the number of IL‐10 + and IL‐10 + IL‐17A + cells via de novo induction of IL‐10. T‐cell cultures differentiated in the presence of G‐1 secreted threefold more IL‐10, with no change in IL‐17A, tumour necrosis factor‐α, or interferon‐γ. Moreover, inhibition of extracellular signal‐regulated kinase (but not p38 or Jun N‐terminal kinase) signalling blocked the response, while analysis of Foxp3 and RORγt expression demonstrated increased numbers of IL‐10 + cells in both the Th17 (RORγt + ) and Foxp3 + RORγt + hybrid T‐cell compartments. Our findings translated in vivo as systemic treatment of male mice with G‐1 led to increased IL‐10 secretion from splenocytes following T‐cell receptor cross‐linking. These results demonstrate that G‐1 acts directly on CD4 + T cells, and to our knowledge provide the first example of a synthetic small molecule capable of eliciting IL‐10 expression in Th17 or hybrid T‐cell populations.