NF-kB may also mediate myocardial dysfunction through induction of expression of its target gene iNOS, which plays an important role in sepsis-related hypotension and impaired left ventricular function. Indeed, in the present study, iNOS expression was increased in male hearts, which correlates with their exacerbated cardiac dysfunction under septic insult. In addition to causing the expression of iNOS, NF-kB activation also leads to a pronounced increase in production of inflammatory mediators such as TNF-a and IL-6. In turn, TNF also activates NF-kB through TNF-receptor-associated factors, this increases cytokine production, thus forming a feed-forward mechanism and amplifying the inflammatory reaction. There is good evidence that those inflammatory cytokines play a significant role in the pathogenesis of sepsis-induced cardiac dysfunction. Moreover, clinical studies showed that stimulation of healthy females with LPS or LTA led to lower TNF-a and IL-6 levels in blood than males. Female patients with sepsis had a higher survival rate, which was correlated with lower TNF-a and higher IL-10 levels, while male traumapatients showed higher IL-6 level than females. In experimental studies, cardiomyocyte TNF-a and IL-6 release was markedly lower in female than male rats following burn injury. In addition, female hearts expressed less myocardial TNF-a in isolated hearts subjected to ischemia/reperfusion injury or LPS treatment. Others have suggested that elevated plasma TNF-a and IL-6 induced by trauma-hemorrhage was prevented by estradiol treatment in rats. Consistent with these findings, in our study, female mice, which had better cardiac function following septic insult, expressed less myocardial TNF-a and IL-6 than male mice subjected to LPS/PepG co-administration. Our study demonstrated that the gender dimorphism of cardiac dysfunction in response to septic insults was abolished by the severe injury induced by high dose of LPS /PepG co-administration. This is in line with a report that the inflammatory cytokine response differed more strongly between blood from men and women after low-concentration of LPS stimulation compared with a higher stimulus concentration. Population-based studies on sex dimorphism in mortality after sepsis showed inconsistent results. Some studies reported increased mortality in males, while other studies demonstrated mortality from severe sepsis/sepsis was not affected by gender. The inconsistency may have resulted from multiple factors such as pre-existing co-morbidities. More importantly, our observations of gender dimorphism in cardiac dysfunction responses to different severities of injury may partially explain the conflicting clinical data. It could be argued that the present study did not provide information about proestrus/estrus or diestrus state of estrus cycle in female mice subjected to septic insults. In this regard, a recent study showed that female mice with CLP survived better than male mice that underwent CLP, but the higher survival in females did not correspond.