Chronic estradiol exposure in oophorectomized mice induces a systemic inflammatory disorder that is mediated via TNFα. (54.9)

Abstract

Abstract Estradiol (E2) administration to oophorectomized (Ovx) mice has been shown to induce the expression of IL-1β, IL-6 and TNFα and inducible NO synthase mRNA in macrophages. Here, we investigated the effect of chronic E2 supplementation on immune responses and cytokines. We found that long-term E2 exposure in Ovx mice led to a marked increase in granulocytes in the liver and spleen. Although, E2 exposed Ovx mice had reduced total cellularity of thymus and spleen and reduced CD4+ and CD8+ T cells in the spleen, more splenic T cells from these mice produced IFN-γ and IL-17 as compared to sham-operated and placebo-treated Ovx mice. IFN-γ and IL-17 were also abundantly made by T, NK and NKT cells in the liver of E2-exposed Ovx mice compared to animals in the other two groups. Intriguingly, E2 exposure in Ovx mice led to significant weight loss as compared to sham-operated mice and placebo-treated Ovx mice. Strikingly, the pro-inflammatory cytokine (IFN-γ and IL-17) response, granulocyte accumulation in liver, and weight loss elicited by chronic E2 exposure in Ovx mice were largely abolished by TNFα deficiency. Finally, 54% of chronically E2-exposed Ovx wild-type B6 mice, as compared to none of sham and placebo-Ovx wild-type mice and none of E2-exposed Ovx TNFα-/- mice, died during the study period. Thus, chronic E2 exposure in Ovx mice elicits an inflammatory condition that is mediated, at least in part, by TNFα.