Estriol: a potent regulator of TNF and IL-6 expression in a murine model of endotoxemia.

The increased incidence of autoimmune disease in premenopausal women suggests the involvement of sex steroids in the pathogenesis of these disease processes. The effects of estrogen on autoimmunity and inflammation may involve changes in the secretion of inflammatory mediators by mononuclear phagocytes. Estradiol, for example, has been reported to regulate TNF, IL-6, IL-1 and JE expression. In the present study the effects of the estrogen agonist, estriol, on cytokine expression have been investigated in mice administered a sublethal lipopolysaccharide, LPS, challenge. Pretreatment of mice with pharmacologic doses of estriol, 0.4-2 mg/kg, resulted in a significant increase in serum TNF levels in both control and autoimmune MRL/lpr mice, following LPS challenge. This increase in TNF over the placebo group was blocked by the estrogen antagonist tamoxifen. Estriol treated mice also exhibited a rapid elevation in serum IL-6 levels following LPS challenge with the peak increase occurring 1 hr post LPS. This contrasted with the placebo group in which maximal serum IL-6 levels were detected at 3 hrs post challenge. This shift in the kinetics of IL-6 increase by estriol was inhibited by tamoxifen. The estriol mediated effects of TNF and IL-6 serum levels were consistent with the changes in TNF and IL-6 mRNA observed ex vivo in elicited peritoneal macrophages. Macrophage cultures from estriol treated animals however, did not demonstrate significant differences from the placebo group for TNF or NO secretion following in vitro LPS challenge. These results suggest that the estrogen agonist estriol can have significant quantitative, TNF, and kinetic, IL-6, effects on inflammatory monokines produced in response to an endotoxin challenge.

Estrogen-induced alterations in lipoprotein metabolism in autoimmune MRL/lpr mice.

Estrogen replacement therapy has been demonstrated to shift the lipoprotein profile toward a less atherogenic one with concomitant increases in HDL and reductions in LDL cholesterol and serum triglycerides. Estrogen, however, has also been implicated in playing a significant role in autoimmune disease and may be involved with disease incidence and progression. The MRL/lpr mouse strain represents an autoimmune disease model with features resembling systemic lupus erythematosus including high-titer autoantibodies, glomerulonephritis, and vasculitis. In the present study, the effects of estrogen treatment on serum lipoprotein profiles were investigated by fast protein liquid chromatography in female MRL/lpr mice, in the MRL/++ strain with a milder form of disease, and in control Balb/c mice. Treatment of MRL/lpr mice for periods of 1 week or longer with pharmacologic doses of estrogen resulted in a significant increase in the amount of cholesterol carried on LDL particles. The up to eightfold increase in LDL cholesterol was less significant in the MRL/++ or Balb/c mice. Maximal increases were observed at 1 to 2 mg/kg of estrogen agonists, and the effect on LDL cholesterol increases was inhibited by tamoxifen. The HDL-to-LDL shift in cholesterol observed in estrogen-treated autoimmune mice correlated with an increase in apolipoprotein E, primarily on larger HDL particles. In addition to the increase in LDL cholesterol, hormonal treatment also resulted in a shift in triglycerides from the VLDL to the LDL fraction in both normal and autoimmune mice. These results suggest that pharmacologic doses of estrogen may contribute to cardiovascular disease progression by shifting the relative distribution of cholesterol from HDL to LDL in this murine model of lupus.

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.