The ICE Inhibitor Pralnacasan Prevents DSS-Induced Colitis in C57BL/6 Mice and Suppresses IP-10 mRNA but Not TNF-α mRNA Expression

Abstract

Previously we demonstrated an ameliorating effect of the interleukin-1beta converting enzyme (ICE) inhibitor pralnacasan on dextran sulfate sodium (DSS)-induced colitis. This study investigates the effects of pralnacasan on cytokine expression in DSS-induced colitis. Colitis was induced by oral administration of DSS. Mice were treated intraperitoneally with the ICE inhibitor pralnacasan (50 mg/kg body weight twice daily). Body weight as well as the presence of occult blood or diarrhea was monitored daily. Subgroups were sacrificed at days 4, 8, and 11 after the beginning of DSS application. Cytokine profiles in colonic tissue were analyzed on the protein level by ELISA and on the mRNA level by real time RT-PCR. Administration of DSS led to an increase in IL-18, IL-12, TNF-alpha, and IFN-gamma protein as well as IP-10 and TNF-alpha mRNA. The increase in IL-18 and IFN-gamma was reduced by ICE inhibition. Pralnacasan prevented DSS-induced colitis in C57BL/6 mice. In C57BL/6 mice, the DSS-induced increase in IP-10 mRNA, but not TNF-alpha mRNA, was completely prevented by ICE inhibition. In conclusion, prevention of colitis in C57BL/6 mice was associated with a suppresion of IP-10 mRNA, but not TNF-alpha mRNA expression, indicating that IL-18-mediated cytokine production is a key element in the pathogenesis of DSS-induced colitis.

Nlrp3-dependent IL-1β inhibits CD103+ dendritic cell differentiation in the gut

“…Similar results have been observed in caspase-1-deficient mice or by administration of soluble IL-1Ra antibody, which both led to profound amelioration of DSS-induced colitis (21). In addition, our group has shown that pralnacasan, a small molecule caspase-1 inhibitor, significantly reduced severity of DSS colitis (19,22). Other groups have reported that Casp1 -/-mice have aggravated colonic inflammation (23).…”

Protective and Aggravating Effects of Nlrp3 Inflammasome Activation in IBD Models: Influence of Genetic and Environmental Factors

“…Siegmund et al [23] reported protection of caspase-1 -/-mice from the deleterious effects of DSS administration and our group found that treatment of mice with the caspase-1 inhibitor pralnacasan ameliorated colonic inflammation [24,25] . In contrast, a recent study showed that caspase-1 -/-mice have aggravated colonic inflammation [7] .…”

Protective effect of Clostridium tyrobutyricum in acute dextran sodium sulphate-induced colitis: differential regulation of tumour necrosis factor-α and interleukin-18 in BALB/c and severe combined immunodeficiency mice

“…Indeed, inhibition of caspase-1 by the specific inhibitor pralnacasan [26] attenuated DSS-induced colitis, this effect being mediated by suppression of proinflamatory IL-18 and IFN-g.…”