Estrogen receptor alpha inhibits IL-1beta induction of gene expression in the mouse liver.
Estrogens have been suggested to modulate several inflammatory processes. Here, we show that IL-1beta treatment induced the expression of approximately 75 genes in the liver of ovariectomized mice. 17alpha-Ethinyl estradiol (EE) pretreatment reduced the IL-1beta induction of approximately one third of these genes. Estrogen receptor alpha (ERalpha) was required for this inhibitory activity, because EE inhibition of IL-1beta-stimulated gene expression occurred in ERbeta knockout mice, but not in ERalpha knockout mice. EE treatment induced expression of 40 genes, including the transcriptional repressor short heterodimer partner and prostaglandin D synthase, known modulators of nuclear factor-kappaB signaling. However, the ER agonists genistein and raloxifene both inhibited IL-1beta gene induction without stimulating the expression of prostaglandin D synthase, short heterodimer partner, or other ER-inducible genes, indicating that induction of gene expression was not required for ER inhibition of IL-1beta signaling. Finally, the ability of EE to repress IL-1beta gene induction varied among tissues. For example, EE inhibited IL-1beta induction of lipopolysaccharide-induced c-x-c chemokine (LIX) in the liver, but not in the spleen or lung. The degree of EE repression did not correlate with ER expression. cAMP response element binding protein-binding protein (CBP)/p300 levels also varied between tissues. Together, these results are consistent with a model of in vivo ER interference with IL-1beta signaling through a coactivator-based mechanism.
Evans
Mark J
MJ
Wyeth Research, Collegeville, Pennsylvania 19426, USA. evansm@wyeth.com
Lai
Kehdih
K
Shaw
Lucinda J
LJ
Harnish
Douglas C
DC
Chadwick
Christopher C
CC
D000818:Animals; D002460:Cell Line; D045166:Estradiol Congeners / Q000494:pharmacology; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004997:Ethinyl Estradiol / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D007249:Inflammation / Q000378:metabolism; D007375:Interleukin-1 / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000096:biosynthesis / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D010052:Ovariectomy; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D015533:Transcriptional Activation; D014162:Transfection
D045166:Estradiol Congeners; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D007375:Interleukin-1; D016328:NF-kappa B; D011960:Receptors, Estrogen; D004997:Ethinyl Estradiol