IL-10-deficient mice demonstrate multiple organ failure and increased mortality during Escherichia coli peritonitis despite an accelerated bacterial clearance

To determine the role of endogenous IL-10 in local antibacterial host defen se and in the development of a systemic inflammatory response syndrome duri ng abdominal sepsis, IL-10 gene-deficient (IL-10(-/-)) and wild-type (IL-10 (+/+)) mice received an i.p. injection with Escherichia coli. Peritonitis w as associated with a bacterial dose-dependent increase in IL-10 concentrati ons in peritoneal fluid and plasma. The recovery of E. coli from the perito neal fluid, blood, and lungs was diminished in IL-10(-/-) mice, indicating that endogenous IL-10 impaired bacterial clearance. Despite a lower bacteri al load, IL-10(-/-) mice had higher concentrations of TNF, macrophage infla mmatory protein-2 and keratinocyte in peritoneal fluid and plasma, and demo nstrated more severe multiple organ damage as indicated by clinical chemist ry and histopathology. Furthermore, IL-10(-/-) mice showed an increased neu trophil recruitment to the peritoneal cavity. To examine the role of elevat ed TNF levels in the altered host response in IL-10(-/-) mice, the effect o f a neutralizing anti-TNF mAb was determined. Anti-TNF did not influence th e clearance of E. coli in either IL-10(+/+) or IL-10(-/-) mice. Furthermore , anti-TNF did not affect leukocyte influx in the peritoneal fluid, multipl e organ damage, or survival in IL-10(+/+) mice. In IL-10(-/-) mice, anti-TN F partially attenuated neutrophil recruitment and multiple organ damage, an d prevented the increased lethality. These data suggest that although endog enous IL-10 facilitates the outgrowth and dissemination of bacteria during E. coli peritonitis, it protects mice from lethality by attenuating the dev elopment of a systemic inflammatory response syndrome by a mechanism that i nvolves inhibition of TNF release.