ANTI-INTERLEUKIN-12 THERAPY PROTECTS MICE IN LETHAL ENDOTOXEMIA BUT IMPAIRS BACTERIAL CLEARANCE IN MURINE ESCHERICHIA COLI PERITONEAL SEPSIS
| Autor: | Jack Gauldie, Steven L. Kunkel, Kathy A. Bucknell, Wan C. Tsai, David A. Zisman, Jodi M. Wilkowski, Theodore J. Standiford, Jonathan L. Bramson, Robert M. Strieter |
|---|---|
| Rok vydání: | 1997 |
| Předmět: |
Lipopolysaccharide
medicine.medical_treatment Colony Count Microbial Gene Expression Bacteremia Peritonitis Critical Care and Intensive Care Medicine Proinflammatory cytokine Sepsis Interferon-gamma Mice chemistry.chemical_compound Macrophages Alveolar Escherichia coli medicine Animals Ascitic Fluid RNA Messenger Escherichia coli Infections DNA Primers Base Sequence Tumor Necrosis Factor-alpha business.industry Peritoneal fluid Immunization Passive Interleukin medicine.disease Interleukin-12 Endotoxemia Disease Models Animal Cytokine chemistry Immunology Emergency Medicine Interleukin 12 Female Tumor necrosis factor alpha business |
| Zdroj: | Shock. 8:349-356 |
| ISSN: | 1073-2322 |
| DOI: | 10.1097/00024382-199711000-00006 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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