title: Chemotherapeutic agent CPT-11 eliminates peritoneal resident macrophages by inducing apoptosis.
abstract: CPT-11 (Irinotecan) is a first-line chemotherapeutic agent in clinic, but it may induce side effects including diarrhea and enteritis in patients. The underlying mechanism of CPT-11's intestinal toxicity is unclear. Peritoneal resident macrophages have been reported to be important for the maintenance of intestinal homeostasis. In this study, we evaluated the cytotoxic effects of CPT-11 on mouse peritoneal resident macrophages. CPT-11 was administered intraperitoneally to mice and their peritoneal exudate cells were isolated for evaluation. CPT-11 treatment strikingly decreased the ratio of F4/80(hi)MHCII(low) large peritoneal macrophages (LPMs), which are regarded as prenatally-originated peritoneal resident macrophages. Consistent with this, the transcription factor GATA6 specifically expressed in LPMs was barely detectable in the macrophages from CPT-11-treated mice, indicative of elimination of LPMs. Such elimination of LPMs was at least partly due to CPT-induced apoptosis in macrophages, because inhibition of apoptosis by caspase-3 inhibitor z-DEVD-fmk significantly diminished the loss of GATA6(+) LPMs. As GATA6 is a transcription factor that controls expression of multiple genes regulating peritoneal B-1 cell development and translocation, elimination of GATA6(+) LPMs led to a great reduction in B-1 cells in the peritoneal cavity after CPT-11 treatment. These results indicated that CPT-11-induced apoptosis contributed to the elimination of peritoneal resident macrophages, which might in turn impair the function of peritoneal B-1 cells in maintaining intestinal homeostasis. Our findings may at least partly explain why CPT-11 treatment in cancer patients induces diarrhea and enteritis, which may provide a novel avenue to prevent such side effects.
authors.affiliation: Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou, China.
authors.forename: Mei-Yun
authors.initials: MY
authors.lastname: Huang
authors.affiliation: Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Pan
authors.affiliation: Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou, China.
authors.forename: Yi-Dan
authors.initials: YD
authors.lastname: Liang
authors.affiliation: Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou, China.
authors.forename: Hong-Xia
authors.initials: HX
authors.lastname: Wei
authors.affiliation: Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou, China.
authors.forename: Li-Hui
authors.initials: LH
authors.lastname: Xu
authors.affiliation: Department of Fetal Medicine, The First Affiliated Hospital of Jinan University, Guangzhou, China.
authors.forename: Qing-Bing
authors.initials: QB
authors.lastname: Zha
authors.affiliation: Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou, China. thexh@jnu.edu.cn.
authors.forename: Xian-Hui
authors.initials: XH
authors.lastname: He
authors.affiliation: Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou, China. dongyun1967@aliyun.com.
authors.forename: Dong-Yun
authors.initials: DY
authors.lastname: Ouyang
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000009:adverse effects; D017209:Apoptosis / Q000187:drug effects*; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004751:Enteritis / Q000139:chemically induced; D005260:Female; D007274:Injections, Intraperitoneal; D000077146:Irinotecan; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D000067996:RAW 264.7 Cells
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D002166:Camptothecin
keywords: Apoptosis; B-1 cells; CPT-11; GATA6; Peritoneal resident macrophages