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. 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.
Zisman
D A
DA
Department of Medicine, University of Michigan Medical School, Ann Arbor 48109-0360, USA.
Kunkel
S L
SL
Strieter
R M
RM
Gauldie
J
J
Tsai
W C
WC
Bramson
J
J
Wilkowski
J M
JM
Bucknell
K A
KA
Standiford
T J
TJ
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
D017931:DNA Primers; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma