Differences in innate defense mechanisms in endotoxemia and polymicrobial septic peritonitis.
Loss, reduction, or enhancement of the ability to respond to bacterial lipopolysaccharide (LPS) has no influence on survival of mice in a model of postoperative polymicrobial septic peritonitis induced by cecal ligation and puncture (CLP). This was demonstrated by using either mice with a defective Tlr4 gene, which encodes the critical receptor molecule for LPS responses, or mice deficient for LPS binding protein (LBP) or mice sensitized to LPS by Propionibacterium acnes. Though interleukin-12 (IL-12) and gamma interferon (IFN-gamma) play an important role in the sensitivity to LPS as well as in the resistance to several infections, loss of these cytokine pathways does not affect survival after CLP. Thus, neutralization of neither endogenous IL-12 nor IFN-gamma altered mortality. In addition, IFN-gamma receptor-deficient mice demonstrated the same sensitivity to CLP as mice with a functional IFN-gamma receptor. However, administration of IFN-gamma at the time of operation or pretreatment of both IFN-gamma-sensitive and IFN-gamma-resistant mice with IL-12 significantly enhanced mortality. This indicates that in the present infection model activation of innate defense mechanisms is not dependent on LPS recognition and does not require endogenous IL-12 or IFN-gamma function. Indeed, exogenous application of these two mediators had deleterious effects.
Echtenacher
B
B
Max-Planck-Institute for Immunobiology, Freiburg, Germany.
Freudenberg
M A
MA
Jack
R S
RS
Männel
D N
DN
D000209:Acute-Phase Proteins; D000818:Animals; D001424:Bacterial Infections / Q000276:immunology*; D002352:Carrier Proteins / Q000235:genetics; D002432:Cecum / Q000601:surgery; D029721:Drosophila Proteins; D019446:Endotoxemia / Q000276:immunology* / Q000401:mortality; D007371:Interferon-gamma / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology; D008026:Ligation; D008070:Lipopolysaccharides / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D010538:Peritonitis / Q000276:immunology* / Q000401:mortality; D011183:Postoperative Complications; D011956:Receptors, Cell Surface / Q000235:genetics; D018805:Sepsis / Q000276:immunology* / Q000401:mortality; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D000099231:Lipopolysaccharide-Binding Protein
D000209:Acute-Phase Proteins; D002352:Carrier Proteins; D029721:Drosophila Proteins; D007371:Interferon-gamma; D018664:Interleukin-12; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D000099231:Lipopolysaccharide-Binding Protein