Irinotecan (CPT-11) in combination with
5-fluorouracil and
leucovorin is a first-line
chemotherapy regimen for the treatment of
colorectal cancer; however, its clinical application is limited by the dose-limiting gastrointestinal toxicity of
colitis. In our previous studies, several
bile acids (BAs) were found significantly elevated in the colon of the CPT-11-induced rat
colitis model. On the other hand, NLRP3
inflammasome has been reported to play important roles in mediating
colitis. Interestingly, BA was stated to activate the NLRP3
inflammasome in some studies, while in some other reports, it showed an inhibitory effect. We assumed that the inflammatory status in different circumstances might have contributed to the controversial findings. In this study, we first discovered, under non-inflammatory conditions, that supplementing BA could activate the NLRP3
inflammasome in THP-1-differentiated macrophages and promote
inflammation. In
lipopolysaccharide (LPS)-induced inflammatory macrophages, however, BA inhibited the NLRP3
inflammasome and reduced
inflammation. Further experiments demonstrated that Takeda
G protein-coupled receptor 5 (TGR5) is essential in mediating the inhibitory effect of BA, while phospho-SP1 (p-SP1) is key to the activation. Furthermore, we applied the above findings to ameliorate CPT-11-caused
colitis in rats by inhibiting SP1 with
mithramycin A (MitA) or activating TGR5 using
oleanolic acid (OA). Our findings may shed light on the discovery of effective interventions for reducing dose-limiting
chemotherapy-induced
colitis.