Irinotecan (CPT-11)-induced elevation of bile acids potentiates suppression of IL-10 expression

• CPT-11 is an effective anticancer drug, but induced toxicity limits its application in the clinic.
• CPT-11 decreased IL-10-producing CD4 T cell frequency in intestinal lamina propria lymphocytes.
• CPT-11 altered the composition of bile acid metabolites, notably DCA and TDCA in liver, bile and intestine.
• DCA and TDCA potentiated CPT-11-induced suppression of IL-10 secretion by active CD4+ naive T cells.

Irinotecan (CPT-11) is a first-line anti-colon cancer drug, however; CPT-11-induced toxicity remains a key factor limiting its clinical application. To search for clues to the mechanism of CPT-11-induced toxicity, metabolomics was applied using ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry. Intraperitoneal injection of 50 mg/kg of CPT-11 induced loss of body weight, and intestine toxicity. Changes in gallbladder morphology suggested alterations in bile acid metabolism, as revealed at the molecular level by analysis of the liver, bile, and ileum metabolomes between the vehicle-treated control group and the CPT-11-treated group. Analysis of immune cell populations further showed that CPT-11 treatment significantly decreased the IL-10-producing CD4 T cell frequency in intestinal lamina propria lymphocytes, but not in spleen or mesenteric lymph nodes. In vitro cell culture studies showed that the addition of bile acids deoxycholic acid and taurodeoxycholic acid accelerated the CPT-11-induced suppression of IL-10 secretion by activated CD4+ naive T cells isolated from mouse splenocytes. These results showed that CPT-11 treatment caused metabolic changes in the composition of bile acids that altered CPT-11-induced suppression of IL-10 expression.

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