title: IL-10-deficient mice demonstrate multiple organ failure and increased mortality during Escherichia coli peritonitis despite an accelerated bacterial clearance.
abstract: To determine the role of endogenous IL-10 in local antibacterial host defense and in the development of a systemic inflammatory response syndrome during abdominal sepsis, IL-10 gene-deficient (IL-10(-/-)) and wild-type (IL-10(+/+)) mice received an i.p. injection with Escherichia coli. Peritonitis was associated with a bacterial dose-dependent increase in IL-10 concentrations in peritoneal fluid and plasma. The recovery of E. coli from the peritoneal fluid, blood, and lungs was diminished in IL-10(-/-) mice, indicating that endogenous IL-10 impaired bacterial clearance. Despite a lower bacterial load, IL-10(-/-) mice had higher concentrations of TNF, macrophage inflammatory protein-2 and keratinocyte in peritoneal fluid and plasma, and demonstrated more severe multiple organ damage as indicated by clinical chemistry and histopathology. Furthermore, IL-10(-/-) mice showed an increased neutrophil recruitment to the peritoneal cavity. To examine the role of elevated TNF levels in the altered host response in IL-10(-/-) mice, the effect of a neutralizing anti-TNF mAb was determined. Anti-TNF did not influence the clearance of E. coli in either IL-10(+/+) or IL-10(-/-) mice. Furthermore, anti-TNF did not affect leukocyte influx in the peritoneal fluid, multiple organ damage, or survival in IL-10(+/+) mice. In IL-10(-/-) mice, anti-TNF partially attenuated neutrophil recruitment and multiple organ damage, and prevented the increased lethality. These data suggest that although endogenous IL-10 facilitates the outgrowth and dissemination of bacteria during E. coli peritonitis, it protects mice from lethality by attenuating the development of a systemic inflammatory response syndrome by a mechanism that involves inhibition of TNF release.
authors.affiliation: Department of Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: M E
authors.initials: ME
authors.lastname: Sewnath
authors.forename: D P
authors.initials: DP
authors.lastname: Olszyna
authors.forename: R
authors.initials: R
authors.lastname: Birjmohun
authors.forename: F J
authors.initials: FJ
authors.lastname: ten Kate
authors.forename: D J
authors.initials: DJ
authors.lastname: Gouma
authors.forename: T
authors.initials: T
authors.lastname: van Der Poll
mesh_terms: D000818:Animals; D001202:Ascitic Fluid / Q000276:immunology / Q000378:metabolism; D018925:Chemokines / Q000097:blood / Q000378:metabolism; D015169:Colony Count, Microbial; D004926:Escherichia coli / Q000254:growth & development / Q000276:immunology; D004927:Escherichia coli Infections / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000401:mortality; D007113:Immunity, Innate / Q000235:genetics; D016753:Interleukin-10 / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009102:Multiple Organ Failure / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000401:mortality; D020556:Neutrophil Infiltration / Q000235:genetics / Q000276:immunology; D010529:Peritoneal Cavity / Q000473:pathology; D010538:Peritonitis / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000401:mortality; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000502:physiology
chemical_list: D018925:Chemokines; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10