ANTI-INTERLEUKIN-12 THERAPY PROTECTS MICE IN LETHAL ENDOTOXEMIA BUT IMPAIRS BACTERIAL CLEARANCE IN MURINE ESCHERICHIA-COLI PERITONEAL SEPSIS

The overzealous production of proinflammatory cytokines in sepsis can result in shock, multiorgan dysfunction, and even death. In this study we assessed the role of endogenously produced interleukin (IL)-12 in murine models of endotoxemia and Gram-negative peritoneal sepsis. Init ial studies indicated that intraperitoneal lipopolysaccharide (LPS) ad ministration to mice induced a significant time-dependent increase in plasma, lung, and liver IL-12 levels. Passive immunization with anti-I L-12 serum intraperitoneally before LPS resulted in a marked reduction in plasma levels of tumor necrosis factor and interferon-gamma. Furth ermore, we observed an increase in endotoxin-induced mortality in mice transiently overexpressing murine IL-12 using a recombinant adenovira l vector (Ad5 mIL-12) administered intraperitoneally. Neutralization o f tumor necrosis factor or interferon-gamma in animals overexpressing IL-12 resulted in significant reductions in LPS-induced mortality, sug gesting that the mechanism whereby IL-12 increases LPS-induced mortali ty is primarily mediated by the enhancement of these cytokines. In con trast, we observed no survival benefit in animals passively immunized with anti-IL-12 serum before the intraperitoneal administration of 2 x 10(8) live Escherichia coli. interestingly, there was an approximatel y 70-fold increase in peritoneal fluid E. coli colony-forming units an d the early onset of bacteremia in animals treated with anti-IL-12 ser um, as compared with control animals. These results indicate that IL-1 2 is produced in response to LPS exposure, and the neutralization of t his cytokine improves survival in endotoxin-challenged animals. Howeve r, IL-12 represents an essential component of antibacterial host defen se, as anti-IL-12 therapy results in significant impairment in the hos t's ability to clear Gram-negative bacterial infection.