IL-10-Deficient Mice Demonstrate Multiple Organ Failure and Increased Mortality DuringEscherichia coliPeritonitis 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.

Interleukin‐10 plays a key role in the modulation of neutrophils recruitment and lung inflammation during infection by Streptococcus pneumoniae

“…These results correlate with previous studies, in which IL-10 À/À mice show an over-reactive immune response against pathogenic microorganisms. 29,37,38 Another explanation is that IL-10 promotes lung permeability and bacterial dissemination from lungs to other organs via systemic circulation; however, this hypothesis has not been tested.…”

STAT‐1‐mediated repression of monocyte interleukin‐10 gene expression in vivo

“…The successful host response to invading pathogens is a careful balance, and while an excessive pro-inflammatory response has negative consequences for the host, overabundant IL-10 can compromise inflammation designed to clear invading pathogens [17]. In vitro, two transcription factors designated SP1 and SP3 have been implicated as important for the regulation of IL-10, suggesting that IL-10 mRNA may be constitutively produced under the influence of SP1/SP3 transcriptional elements and largely regulated by post-transcriptional control mechanisms such as 3 0 mRNA instability sequences present in the IL-10 mRNA transcript [18][19][20].…”

IL-10 Acts As a Developmental Switch Guiding Monocyte Differentiation to Macrophages during a Murine Peritoneal Infection

“…with a sublethal dose, which was an amount equivalent to 15 mg CC. Because mice deficient in IL-10 or the IL-10R1 are highly susceptible to peritonitis, experiments that included these animals were conducted using 2 mg CC (13,14). In some experiments 0.5 ml 4% Brewer thioglycollate medium was used to induce a sterile peritoneal inflammation.…”