Tumor necrosis factor-alpha suppresses the expression of steroid receptor coactivator-1 and -2: a possible mechanism contributing to changes in steroid hormone responsiveness.
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-alpha 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-alpha effects on steroid hormone-mediated transcriptional activity, UtSMC were transfected with progesterone receptor B (PR-B) and a model PRE2-luciferase reporter construct. Transfected UtSMC were treated with progesterone alone or in the presence of TNF-alpha, and assayed for luciferase activity. TNF-alpha (10 ng/ml) diminished progesterone-stimulated PR-B-mediated transactivation by approximately 60% (P<0.02). The TNF-alpha-dependent decrease in PRE-luciferase activity was fully prevented by cotransfection with SRC-2, and partially prevented with exogenous SRC-1. In conclusion, TNF-alpha 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.
Leite
Rita S
RS
Center for Research on Reproduction and Women's Health, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Brown
Amy G
AG
Strauss
Jerome F
JF
D015536:Down-Regulation / Q000187:drug effects*; D005260:Female; D051548:Histone Acetyltransferases; D006801:Humans; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D056920:Nuclear Receptor Coactivator 1; D051958:Nuclear Receptor Coactivator 2; D011374:Progesterone / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014599:Uterus / Q000166:cytology
D051958:Nuclear Receptor Coactivator 2; D012333:RNA, Messenger; D011980:Receptors, Progesterone; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; C097314:progesterone receptor B; D011374:Progesterone; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; D056920:Nuclear Receptor Coactivator 1