Mechanism of the salutary effects of 17β-estradiol following trauma-hemorrhage: Direct downregulation of Kupffer cell proinflammatory cytokine production

Kupffer cells have been reported as a major source of proinflammatory cytokines (i.e. IL-6, TNF-α), which have been implicated in the pathogenesis of trauma-hemorrhage. Previous studies have shown a protective effect of 17β-estradiol on immune function and physiological responses following trauma-hemorrhage. In this study, we investigated whether 17β-estradiol has a direct effect on Kupffer cell cytokine production following trauma-hemorrhage. Male Sprague-Dawley rats were subjected to trauma (midline laparotomy) and hemorrhage (35-40 mmHg for 90 min followed by fluid resuscitation) or sham operation. Two hours later, Kupffer cells were isolated and cultured with 17β-estradiol in the presence and absence of lipopolysaccharide stimulation. Kupffer cell IL-6 and TNF-α production increased following trauma-hemorrhage. Incubation with 17β-estradiol attenuated the production of IL-6 by cells from both sham and trauma-hemorrhage animals in a dose-dependent manner. The suppression of IL-6 production by 17β-estradiol was paralleled by a decrease in mRNA levels. In contrast to IL-6, the effects of 17β-estradiol on TNF-α production were minimal. In conclusion, these results indicate the direct downregulation of Kupffer cell IL-6 production by 17β-estradiol at a molecular level, which might explain in part the previously observed salutary effects of estradiol treatment following trauma-hemorrhage.