Sexual dimorphism exists in the immune response. Both humoral and cell-mediated immunity are more active in females than in males, and steroid gonadal hormones may play an important role in regulating this response. We have documented gender differences in several aspects of neutrophil and macrophage functions elicited by lipopolysaccharide (LPS) (endotoxin) treatment and/or acute ethanol intoxication. In LPS-treated female rats, circulating neutrophils and alveolar macrophages are resistant to the deleterious effects of surgery and anesthesia on phagocytosis observed in male rats. The generation of cytokine-induced neutrophil chemoattractant (CINC) by hepatocytes and Kupffer cells of LPS-treated rats, as well as TNF-alpha secretion by Kupffer cells and alveolar macrophages of acutely ethanol intoxicated rats are also gender dependent. The effects of alcohol on the immune response are expressed differently in males and females. In LPS plus ethanol-treated rats gender differences were noted in terms of adhesion molecule (CD11b/c) expression on circulating neutrophils, and cytoskeletal reorganization in blood-recruited neutrophils and Kupffer cells. Nitric oxide (NO) plays an important role in inflammatory processes. We found gender differences in NO production by alveolar macrophages of LPS-treated rats; this difference was abrogated by ethanol treatment. LPS tolerance and ethanol treatment modulate hepatic NO production in rats in a cell- and gender-dependent fashion, which may exert a protective influence against oxidative injury in the female liver.

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Some disease processes in which increased endotoxin and cytokine levels exist (e.g., sepsis and infantile diarrhea) are also associated with increased levels of blood nitrates, the stable end products of nitric oxide. Available evidence suggests that the effects of an endotoxic environment, with its attendant complex cytokine networks, on liver function are mediated in part by modulation of hepatic nitric oxide synthesis. This hypothesis was tested by means of studying nitric oxide formation and its regulation in liver parenchymal and nonparenchymal cells of rats that had been continuously infused with endotoxin for 30 hr. Hepatocytes of such rats responded to in vitro stimulation for 20 hr by single cytokines, tumor necrosis factor, interleukin-1 beta and interferon-gamma with enhanced nitric oxide formation. In combination, interferon-gamma and endotoxin had greater synergistic effect on hepatocytes than did tumor necrosis factor and endotoxin. Kupffer cells of these endotoxic rats responded to 20 hr of interferon-gamma stimulation with the same enhanced nitric oxide formation we documented previously for endotoxin. Potentiation of the effect, through combination of endotoxin and interferon-gamma, was not as marked as it was with hepatocytes. Challenge of Kupffer cells with tumor necrosis factor or interleukin-1 beta evoked no response. Hepatocytes and Kupffer cells of time-matched, saline solution-treated rats were unresponsive to endotoxin or cytokine stimulation. Small quantities of nitric oxide were produced by endothelial cells spontaneously; this production was somewhat enhanced in cells of the endotoxin-infused rats by a 20-hr in vitro endotoxin challenge. Studies with inhibitors suggest that enhanced nitric oxide formation by endotoxic hepatocytes and Kupffer cells in response to in vitro endotoxin stimulation is differentially regulated. Our findings indicate modulation of nitric oxide generation by cytokines in vitro in various liver cell types of endotoxic rats. A similar scenario may exist in vivo because of the prevailing inflammatory response to endotoxin administration.