title: Anti-interleukin-12 therapy protects mice in lethal endotoxemia but impairs bacterial clearance in murine Escherichia coli peritoneal sepsis.
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.affiliation: Department of Medicine, University of Michigan Medical School, Ann Arbor 48109-0360, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Zisman
authors.forename: S L
authors.initials: SL
authors.lastname: Kunkel
authors.forename: R M
authors.initials: RM
authors.lastname: Strieter
authors.forename: J
authors.initials: J
authors.lastname: Gauldie
authors.forename: W C
authors.initials: WC
authors.lastname: Tsai
authors.forename: J
authors.initials: J
authors.lastname: Bramson
authors.forename: J M
authors.initials: JM
authors.lastname: Wilkowski
authors.forename: K A
authors.initials: KA
authors.lastname: Bucknell
authors.forename: T J
authors.initials: TJ
authors.lastname: Standiford
mesh_terms: D000818:Animals; D001202:Ascitic Fluid / Q000382:microbiology; D016470:Bacteremia / Q000209:etiology / Q000276:immunology; D001483:Base Sequence; D015169:Colony Count, Microbial; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000209:etiology / Q000276:immunology / Q000517:prevention & control*; D004926:Escherichia coli / Q000276:immunology / Q000302:isolation & purification; D004927:Escherichia coli Infections / Q000276:immunology* / Q000382:microbiology; D005260:Female; D015870:Gene Expression; D007116:Immunization, Passive; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D018664:Interleukin-12 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D016676:Macrophages, Alveolar / Q000276:immunology; D051379:Mice; D010538:Peritonitis / Q000276:immunology* / Q000382:microbiology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018805:Sepsis / Q000276:immunology* / Q000382:microbiology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology
chemical_list: D017931:DNA Primers; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma