Die Rolle von IL-12 und IL-18 in der murinen intraabdominellen Sepsis

Abstract

Abdominal sepsis remains the major cause of postoperative mortality in SICUs. The animal model of abdominal sepsis colon ascendens stent peritonitis (CASP) closely resembles the course of human patients suffering from peritonitis and sepsis caused by anastomosis insufficiency after major abdominal surgery. High levels of host derived inflammatory cytokines such as TNF-α and IFN-γ are thought to be at least partially detrimental factors in sepsis. However, we previously showed that IFN-γ is essential for survival after CASP surgery. IL-12 and IL-18 are both cytokines which are known to efficiently induce IFN-γ production in vitro and in vivo. The aim of this study was to characterize the role of IL-12 and IL-18 on survival after CASP surgery. CASP surgery was performed using either IL-12P40 deficient mice or mice treated with neutralizing antibodies directed against IL-18. The survival rate was compared to control mice. Various tissues were harvested 3 and 12 h after CASP surgery. RNAse protection assay for gene transcription was performed. Survival analysis revealed a remarkably increased lethality among IL-12p40-/- mice and anti-IL-18 treated mice as compared to the controls. Analysis of IL-12p40-/- CASP mice revealed a strongly delayed and reduced upregulation of cytokine and chemokine transcription in lung and liver of IL-12 deficient mice compared to wild type controls. In CASP mice treated with neutralizing polyclonal antibodies against IL-18 the transcription rate of cytokines and chemokines was clearly impaired. Additionally, an increased bacterial load was found in anti-IL-18 treated mice 16 h after CASP surgery as compared to the controls. Together, these results demonstrate a crucial role of IL-12 and IL-18 on the survival of abdominal sepsis.