Estrogen Receptor Inhibits IL-1 Induction of Gene Expression in the Mouse Liver

Abstract

Estrogens have been suggested to modulate several inflammatory processes. Here, we show that IL-1 treatment induced the expression of approximately 75 genes in the liver of ovariectomized mice. 17-Ethinyl estradiol (EE) pretreatment reduced the IL-1 induction of approximately one third of these genes. Estrogen receptor (ER) was required for this inhibitory activity, because EE inhibition of IL-1-stimulated gene expression occurred in ER knockout mice, but not in ER 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-B signaling. However, the ER agonists genistein and raloxifene both inhibited IL-1 gene induction without stimulating the expression of prostaglandin D synthase, short heterodimer partner, or other ERinducible genes, indicating that induction of gene expression was not required for ER inhibition of IL-1 signaling. Finally, the ability of EE to repress IL-1 gene induction varied among tissues. For example, EE inhibited IL-1 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-1 signaling through a coactivatorbased mechanism. (Endocrinology 143: 2559–2570, 2002) EPSIS IS THE 11th leading cause of death in the United States and is a major cause of mortality in the intensive care unit, with mortality rates of 40 – 60% (1). The initial manifestation of sepsis is extensive inflammation, primarily due to increased TNF, IL-1, and IL-6 levels (2) resulting from bacterial products such as lipopolysaccharides (LPS). Animal models of sepsis have suggested that anticytokine therapy could provide benefit in sepsis (3). However, several randomized clinical trials of antiinflammatory therapies, including the use of naturally occurring antagonists or blocking antibodies directed against TNF or IL-1, have not shown any improvement in survival from sepsis (1), perhaps due to the redundant nature of cytokine signaling pathways. In humans, gender has recently been shown to be a significant predictor of survival from sepsis, with a hospital mortality rate of 70% for male patients, but only 26% for female patients in a prospective study (4). Surprisingly, although the women studied in this trial were postmenopausal, their plasma levels of 17-estradiol were in the high normal physiological range (250 pg/ml) and were significantly higher than those in the male patients, possibly due to