Abstract
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.
© 2011 The Authors. Immunology © 2011 Blackwell Publishing Ltd.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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CD4-Positive T-Lymphocytes / drug effects
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / metabolism
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Cell Proliferation / drug effects
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Cyclopentanes / pharmacology*
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Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Forkhead Transcription Factors / metabolism
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Green Fluorescent Proteins / genetics
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Interferon-gamma / metabolism
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Interleukin-10 / metabolism*
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Interleukin-17 / metabolism
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Interleukin-23 / pharmacology
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Interleukin-6 / metabolism
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Interleukin-6 / pharmacology
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Lymphocyte Activation / drug effects
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Lymphocyte Activation / immunology
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
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Quinolines / pharmacology*
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Receptors, Estrogen
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Receptors, G-Protein-Coupled / agonists*
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Receptors, G-Protein-Coupled / antagonists & inhibitors
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Receptors, G-Protein-Coupled / metabolism
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Signal Transduction / drug effects
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Signal Transduction / immunology
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Spleen / cytology
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Spleen / drug effects
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Spleen / immunology
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T-Lymphocyte Subsets / drug effects
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T-Lymphocyte Subsets / immunology
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T-Lymphocyte Subsets / metabolism
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T-Lymphocytes / drug effects
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism
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Th17 Cells / drug effects*
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Th17 Cells / immunology
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Th17 Cells / metabolism*
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Transforming Growth Factor beta / pharmacology
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Tumor Necrosis Factor-alpha / metabolism
Substances
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1-(4-(6-bromobenzo(1,3)dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta(c)quinolin-8-yl)ethanone
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Cyclopentanes
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Forkhead Transcription Factors
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Foxp3 protein, mouse
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GPER1 protein, mouse
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IL10 protein, mouse
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Interleukin-17
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Interleukin-23
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Interleukin-6
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Nuclear Receptor Subfamily 1, Group F, Member 3
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Quinolines
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Receptors, Estrogen
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Receptors, G-Protein-Coupled
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Transforming Growth Factor beta
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Tumor Necrosis Factor-alpha
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enhanced green fluorescent protein
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Interleukin-10
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Green Fluorescent Proteins
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Interferon-gamma
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Extracellular Signal-Regulated MAP Kinases