17β-Estradiol attenuates cytokine-induced nitric oxide production in rat hepatocyte

Nitric oxide (NO) regulation during shock and sepsis is complex. NO production by endothelial NO synthase maintains microvascular perfusion and prevents shock-induced organ injury. However, the overproduction of NO by inducible NO synthase (iNOS) contributes to liver dysfunction after shock and is associated with increased tissue damage and mortality. Estrogen improves organ function and outcome after shock and sepsis, but the mechanism is unknown. We hypothesized that 17β-estradiol would improve organ function by regulating the production of hepatocyte NO. Isolated rat hepatocytes were stimulated in vitro with pro-inflammatory cytokines to induce NO synthesis with or without estrogen. Nitrite was detected after 24 hours. INOS protein was determined using Western blot analysis. Cytokine stimulation increased nitrite and iNOS protein in a dose-dependent manner. The cytokine-induced nitrite increase was significantly decreased by estrogen. iNOS expression was also diminished in cultures with the higher doses of estrogen. 17β-Estradiol decreases cytokine-stimulated iNOS expression and NO production. The down-regulation of iNOS expression may account for the beneficial role of estrogens in models of sepsis and shock.