Document Detail


Induction of interleukin-10 in the T helper type 17 effector population by the G protein coupled estrogen receptor (GPER) agonist G-1.
MedLine Citation:
PMID:  21722102     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Ryan L Brunsing; Eric R Prossnitz
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-07-02
Journal Detail:
Title:  Immunology     Volume:  134     ISSN:  1365-2567     ISO Abbreviation:  Immunology     Publication Date:  2011 Sep 
Date Detail:
Created Date:  2011-08-09     Completed Date:  2011-10-13     Revised Date:  2014-09-13    
Medline Journal Info:
Nlm Unique ID:  0374672     Medline TA:  Immunology     Country:  England    
Other Details:
Languages:  eng     Pagination:  93-106     Citation Subset:  IM    
Copyright Information:
© 2011 The Authors. Immunology © 2011 Blackwell Publishing Ltd.
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MeSH Terms
Descriptor/Qualifier:
Animals
CD4-Positive T-Lymphocytes / drug effects,  immunology,  metabolism
Cell Proliferation / drug effects
Cyclopentanes / pharmacology*
Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors,  metabolism
Forkhead Transcription Factors / metabolism
Green Fluorescent Proteins / genetics
Interferon-gamma / metabolism
Interleukin-10 / metabolism*
Interleukin-17 / metabolism
Interleukin-23 / pharmacology
Interleukin-6 / metabolism,  pharmacology
Lymphocyte Activation / drug effects,  immunology
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
Quinolines / pharmacology*
Receptors, G-Protein-Coupled / agonists*,  antagonists & inhibitors,  metabolism
Signal Transduction / drug effects,  immunology
Spleen / cytology,  drug effects,  immunology
T-Lymphocyte Subsets / drug effects,  immunology,  metabolism
T-Lymphocytes / drug effects,  immunology,  metabolism
Th17 Cells / drug effects*,  immunology,  metabolism*
Transforming Growth Factor beta / pharmacology
Tumor Necrosis Factor-alpha / metabolism
Grant Support
ID/Acronym/Agency:
CA118743/CA/NCI NIH HHS; CA127731/CA/NCI NIH HHS; P30 CA118100/CA/NCI NIH HHS; R01 CA116662/CA/NCI NIH HHS; R01 CA127731/CA/NCI NIH HHS; T32 AI007538/AI/NIAID NIH HHS
Chemical
Reg. No./Substance:
0/1-(4-(6-bromobenzo(1,3)dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta(c)quinolin-8-yl)ethanone; 0/Cyclopentanes; 0/Forkhead Transcription Factors; 0/Foxp3 protein, mouse; 0/GPR30 protein, mouse; 0/IL10 protein, mouse; 0/Interleukin-17; 0/Interleukin-23; 0/Interleukin-6; 0/Nuclear Receptor Subfamily 1, Group F, Member 3; 0/Quinolines; 0/Receptors, G-Protein-Coupled; 0/Transforming Growth Factor beta; 0/Tumor Necrosis Factor-alpha; 0/enhanced green fluorescent protein; 130068-27-8/Interleukin-10; 147336-22-9/Green Fluorescent Proteins; 82115-62-6/Interferon-gamma; EC 2.7.11.24/Extracellular Signal-Regulated MAP Kinases
Comments/Corrections

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