Impact of interleukin-12, oxidative burst, and iNOS on the survival of murine fecal peritonitis

Abstract

Abdominal sepsis due to secondary fecal peritonitis following anastomosis insufficiency is a rare but life threatening complication of colorectal surgery. The induction of IFN-gamma by IL-12 is believed to play a key role in sepsis as it promotes antibacterial effector mechanisms such as oxidative burst or nitric oxide induction. The impact of gene deficiency for IL-12 (IL-12p40 KO), oxidative burst (p47(phox) KO), or NO induction (iNOS KO) on the outcome of fecal peritonitis was characterized using the murine Colon Ascendens Stent Peritonitis model (CASP). In the IL-12p40 KO model, 3 and 12 h after surgery, serum cytokine levels of IL-1beta, TNF, IL-18, and IL-10 were analyzed. Expression of IL-1beta, IL-10, IP-10, and MIP-1alpha was measured in lung and liver by RNAse Protection Assay. IL-12p40 and iNOS-deficient mice exhibited a significantly higher susceptibility to CASP as compared to the controls, whereas no significant difference was observed in p47(phox) KO mice. Absence of IL-12 resulted in delayed expression of proinflammatory cytokines and chemokines in both the liver and the lung, and was associated with significant reduction of IL-1beta levels in the serum 12 h after CASP. IL-12 and iNOS possess protective functions in fecal murine peritonitis. Surprisingly, no significant contribution of oxidative burst to the immune response was observed. Overall, these findings suggest that IL-12 deficiency causes a profound delay of the immune response after polymicrobial challenge resulting in significantly increased susceptibility in the CASP model.

Selective Depletion of Alveolar Macrophages in Polymicrobial Sepsis Increases Lung Injury, Bacterial Load and Mortality but Does Not Affect Cytokine Release

“…All mediators were strongly increased in the serum of septic mice in comparison with the control groups showing systemic inflammation. This result fits well with previous findings in the CASP model [6, 23, 28]. However, no difference could be observed between Lipo-clod and Lipo-PBS-treated animals demonstrating that systemic cytokine release appears to be independent of AM in the context of sepsis.…”

Seasonal variations in inflammatory responses to sepsis and stress in mice*

“…These experiments were originally designed to the following purposes: sepsis survival analysis and cytokine levels in the context of an anti-inflammatory influence of the vagus nerve (28), studies on interleukin-12, oxidative burst, and inducible nitric oxide synthase (29), the comparison of two sepsis models (14), strain and sex-specific differences of stress susceptibility (8), and the comparison of CASP, lipopolysaccharide shock, and mild cecal ligation and puncture in stress-preconditioned mice (30).…”

Increased inflammation and lethality of Dusp1−/− mice in polymicrobial peritonitis models

“…In the CASP model TNF is not protective, instead a lack of interferon-c (IFN-c) and its inducer IL-12 are detrimental. 13,15,16 On the other hand, the production of the anti-inflammatory IL-10 early after sepsis induction is required in both CLP and CASP to prevent excess death probably as the result of acute hyper-inflammation. 17,18 Here, we have investigated the phenotype of Dusp1 )/) mice in the CLP and CASP models of polymicrobial peritonitis.…”