In vivo modulation of murine serum tumour necrosis factor and interleukin-6 levels during endotoxemia by oestrogen agonists and antagonists

Oestrogen has been reported to modulate tumour necrosis factor (TNF), interleukin (IL)-1 and IL-6 cytokine levels in human mononuclear cell cultures. In the present study, the effects of exogenous oestrogen administration on the cytokine response to an endotoxin challenge was investigated in a murine model of endotoxemia. Animals pretreated for 4 days with 17 alpha ethinyl oestradiol exhibited divergent regulation of TNF and IL-6 levels in sera from endotoxin-stimulated mice. Oestrogen treatment resulted in a significant increase in serum TNF while serum IL-6 levels, relative to the placebo group, decreased in response to an endotoxin challenge. These oestrogenic effects were dose dependent with maximal elevations observed in TNF at 1 mg/kg and maximal reduction in IL-6 at 0.1 mg/kg of 17 alpha ethinyl oestradiol. The increase in TNF levels by ethinyl oestradiol was blocked by co-administration of the oestrogen receptor antagonist tamoxifen. Oestrogen-mediated modulation of the TNF and IL-6 response to endotoxin was also apparent in animals implanted with 17 beta oestradiol pellets. The oestrogen-mediated effects on serum IL-6 were consistent with a reduction in IL-6 mRNA in peritoneal macrophages from oestrogen-treated mice. The effects of oestrogen on TNF and IL-6 production were also investigated in vitro. Oestradiol-treated macrophage cultures produced three- to fourfold lower amounts of IL-6 without any significant modulatory effects on TNF secretion. The combined in vivo and in vitro results demonstrate the modulation of IL-6 and TNF during endotoxemia by oestrogen analogues through an oestrogen receptor-dependent mechanism.