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

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abstract

  • 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. Initial studies indicated that intraperitoneal lipopolysaccharide (LPS) administration to mice induced a significant time-dependent increase in plasma, lung, and liver IL-12 levels. Passive immunization with anti-IL-12 serum intraperitoneally before LPS resulted in a marked reduction in plasma levels of tumor necrosis factor and interferon-gamma. Furthermore, we observed an increase in endotoxin-induced mortality in mice transiently overexpressing murine IL-12 using a recombinant adenoviral vector (Ad5 mIL-12) administered intraperitoneally. Neutralization of tumor necrosis factor or interferon-gamma in animals overexpressing IL-12 resulted in significant reductions in LPS-induced mortality, suggesting that the mechanism whereby IL-12 increases LPS-induced mortality is primarily mediated by the enhancement of these cytokines. In contrast, 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 approximately 70-fold increase in peritoneal fluid E. coli colony-forming units and the early onset of bacteremia in animals treated with anti-IL-12 serum, as compared with control animals. These results indicate that IL-12 is produced in response to LPS exposure, and the neutralization of this cytokine improves survival in endotoxin-challenged animals. However, IL-12 represents an essential component of antibacterial host defense, as anti-IL-12 therapy results in significant impairment in the host's ability to clear Gram-negative bacterial infection.

authors

  • Zisman, David A
  • Kunkel, Steven L
  • Strieter, Robert M
  • Gauldie, Jack
  • Tsai, Wan C
  • Bramson, Jonathan
  • Wilkowski, Jodi M
  • Bucknell, Kathy A
  • Standiford, Theodore J

publication date

  • November 1997

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