Oral administration of the immunomodulator JBT-3002 induces endogenous interleukin 15 in intestinal macrophages for protection against irinotecan-mediated destruction of intestinal epithelium

We recently reported that p.o. administration of the new synthetic bacteria l Lipopeptide JBT-3002 can protect mice from irinotecan (CPT-11)-induced in testinal injury, but the mechanism was not known, Because interleukin-15 (I L-15) is associated with maintenance of intestinal epithelial cell integrit y, we examined whether p.o. administration of JET-3002 elevates expression of this monocyte-derived cytokine. Four daily i.p. injections of 100 mg/kg CPT-11 were effective against liver metastases produced by CT-26 murine col on cancer cells, but severe damage to the intestinal epithelium and early d eath of the mice also resulted. Three consecutive daily p.o. doses of JET-3 002 prior to i.p. injection of irinotecan prevented the undesirable side ef fects of irinotecan without reducing its ability to eradicate liver metasta ses. Immunohistochemical analyses of the intestines of mice treated with JE T-3002 and CPT-11 demonstrated an increase in the number of dividing cells in the crypts and enhanced expression of IL-15 in lamina propria cells; the increase correlated with increased expression of the IL-15 gene as determi ned by semiquantitative reverse transcriptase-PCR, In vitro studies demonst rated that JET-3002 induced expression of IL-15 in peritoneal macrophages b ut not in normal intestinal epithelial cells (IEC-6), Moreover, the presenc e of IL-15 decreased irinotecan-mediated cytotoxicity of IEC-6 epithelial c ells. These data show that the p.o. administration of JET-3002 induces expr ession of IL-15 by macrophages in the lamina propria, which can prevent iri notecan-induced injury to the intestinal mucosa.