Differences in innate defense mechanisms in endotoxemia and polymicrobial septic peritonitis

Loss, reduction, or enhancement of the ability to respond to bacterial lipo polysaccharide (LPS) has no influence on survival of mice in a model of pos toperative polymicrobial septic peritonitis induced by cecal ligation and p uncture (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 b y Propionibacterium aches. Though interleukin-12 (IL-12) and gamma interfer on (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 do es not affect survival after CLP. Thus, neutralization of neither endogenou s IL-12 nor IFN-gamma altered mortality. In addition, IFN-gamma receptor-de ficient mice demonstrated the same sensitivity to CLP as mice with a functi onal IFN-gamma receptor. However, administration of IFN-gamma at the time o f operation or pretreatment of both IFN-gamma -sensitive and IFN-gamma -res istant mice with IL-12 significantly enhanced mortality. This indicates tha t 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 ha d deleterious effects.