TNF-related apoptosis-inducing ligand deficiency enhances survival in murine colon ascendens stent peritonitis

Abstract

BackgroundApart from inducing apoptosis in tumor cells, tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) influences inflammatory reactions. Murine colon ascendens stent peritonitis (CASP) represents a model of diffuse peritonitis. Recently, it has been demonstrated that administration of exogenous TRAIL not only induces apoptosis in neutrophils but also enhances survival in this model. The aim of this study was to examine the impact of genetic TRAIL deficiency on the course of CASP.MethodsPeritonitis was induced in 6- to 8-week-old female TRAIL−/− mice as well as in wild-type mice. The sepsis severity score and survival of mice were monitored. Bacterial loads in blood as well as in the lymphoid organs were examined. Additionally, the number of apoptotic cells within the lymphoid organs was determined.ResultsAs early as 8 hours postinduction of CASP, TRAIL−/− mice were significantly more affected by sepsis than wild-type mice, as measured by the sepsis severity score. However, during the further course of sepsis, TRAIL deficiency led to significantly decreased sepsis severity scores, resulting in an enhanced overall survival in TRAIL−/− mice. The better survival of TRAIL−/− mice was accompanied by a decreased bacterial load within the blood. In marked contrast, the number of apoptotic cells within the lymphoid organs was highly increased in TRAIL−/− mice 20 hours after induction of CASP.ConclusionHence, exogenous and endogenous TRAIL is protective during the early phase of sepsis, while endogenous TRAIL appears to be detrimental in the later course of this disease.

CASP-Model Sepsis Triggers Systemic Innate Immune Responses Revealed by the Systems-Level Signaling Pathways

“…Moreover, the complex phenotypic syndromes, born by the identified and characterized 21 (KO MyD88-associated) target signaling pathways, contributed to the rapid progression of severe sepsis and even possible emerging death from complicated syndromes in post-operative mice, much beyond what has been perceived in literature ( 24 ). Our results update a significant advance in understanding the CASP-model sepsis mechanisms that have been explored for decades ( 4 , 8 , 24 , 27 , 31 , 52 – 56 ).…”

Interactions of Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand (TRAIL) with the Immune System: Implications for Inflammation and Cancer

“…The pleiotropic effects of TRAIL on neutrophils and on T cells lead to conflicting results in peritonitis models and are a possible explanation for the sometimes seemingly contradictory results derived from infection models. Thus, TRAIL −/− mice display a survival advantage in a murine model of polymicrobial sepsis, an observation that is independent from neutrophils [79]. In concordance with these results, Gurung et al found that TRAIL −/− mice were better able to control a second-hit infection following peritonitis, suggesting that sepsis-induced immunosuppression was TRAIL-dependent.…”

LPS promotes resistance to TRAIL-induced apoptosis in pancreatic cancer

“…However, more recently it has been discovered that TRAIL also exerts a negative impact on immune cells [27, 29, 30] demonstrating promotion of tumour growth in a murine model of pancreatic cancer [31]. …”

“…TRAIL is a member of the TNF superfamily and was initially thought to selectively induce apoptosis in cancer cells [ 28 ]. However, more recently it has been discovered that TRAIL also exerts a negative impact on immune cells [ 27 , 29 , 30 ] demonstrating promotion of tumour growth in a murine model of pancreatic cancer [ 31 ].…”