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Tumor necrosis factor‐α suppresses the expression of steroid receptor coactivator‐1 and ‐2: A possible mechanism contributing to changes in steroid hormone responsiveness
Author(s) -
Leite Rita S.,
Brown Amy G.,
Strauss Jerome F.
Publication year - 2004
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.04-1684fje
Subject(s) - transactivation , coactivator , endocrinology , medicine , steroid hormone , proinflammatory cytokine , receptor , steroid hormone receptor , tumor necrosis factor alpha , transfection , nuclear receptor , chemistry , hormone , biology , inflammation , gene expression , transcription factor , cancer , biochemistry , estrogen receptor , breast cancer , gene
Inflammation is associated in some tissues with diminished responsiveness to steroid hormone action. We hypothesized that proinflammatory cytokines alter steroid hormone sensitivity, in part, by reducing levels of key nuclear receptor coactivators. Treatment of cultured human uterine smooth muscle cells (UtSMC) with TNF‐α significantly reduced mRNA for the coactivators, SRC‐1 (42%, P <0.01) and 2 (47%, P <0.03), and diminished the respective protein levels, but did not significantly alter the mRNAs encoding SRC‐3, CBP and the corepressors, NCoR and SMRT; or progesterone receptor protein levels. To assess TNF‐α effects on steroid hormone‐mediated transcriptional activity, UtSMC were transfected with progesterone receptor B (PR‐B) and a model PRE(2)‐luciferase reporter construct. Transfected UtSMC were treated with progesterone alone or in the presence of TNF‐α, and assayed for luciferase activity. TNF‐α (10 ng/ml) diminished progesterone‐stimulated PR‐B‐mediated transactivation by ~60% ( P <0.02). The TNF‐α‐dependent decrease in PRE‐luciferase activity was fully prevented by cotransfection with SRC‐2, and partially prevented with exogenous SRC‐1. In conclusion, TNF‐α impairs progesterone‐stimulated PR‐B‐mediated transactivation, and these effects appear to be due, in part, to reduced expression of SRC‐1 and ‐2, which is a novel mechanism by which inflammation can functionally block steroid hormone action.