title: IL-1Ra selectively protects intestinal crypt epithelial cells, but not tumor cells, from chemotoxicity via p53-mediated upregulation of p21(WAF1) and p27(KIP1.).
abstract: Chemotherapy-induced intestinal mucositis (CIM) is a major dose-limiting side effect, resulting from the nonspecific cytoablative actions of chemoagents, including 5-fluorouracil (5-FU) and irinotecan (CPT-11). Preventive strategies are urgently needed for the predictable CIM. Previously, we have demonstrated an important role of recombinant human interleukin-1 receptor antagonist (rhIL-1Ra) in the prevention of cyclophosphamide-induced mucositis in mice. In this study, the preventive role of rhIL-1Ra was further evaluated in 5-FU- and CPT-11-induced mucositis mouse models. rhIL-1Ra pretreatment reduced the incidence, severity, and duration of chemotherapy-induced diarrhea, through attenuating crypt apoptosis and improving crypt survival in wild-type mice, but not in IL-1RI(-/-), p53(-/-), and p21(-/-) mice. Further studies demonstrated that rhIL-1Ra promoted the cell cycle arrest of intestinal crypt epithelia (ICE) through elevating the cellular level of p21(WAF1) and p27(KIP1), which was abolished in IL-1RI(-/-) and p53(-/-) mice, and in p21(WAF1) and p27(KIP1) silenced IEC-6 cells. Importantly, the tumor growth and sensitivity to chemotherapy were not affected by rhIL-1Ra in cultures of tumor cell lines and in a syngeneic tumor-transplantation mouse model. The present study demonstrated that rhIL-1Ra effectively and specifically protected ICE from chemotoxicity through reversible reduction of the basal level of IL-1 signaling to promote normal cell cycle arrest, but not tumor cells. Our findings support the clinical development of rhIL-1Ra in the prevention of CIM.
authors.affiliation: Laboratory of Regeneromics, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Wang
authors.affiliation: Shanghai Municipality Key Laboratory of Veterinary Biotechnology, School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Shunying
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Laboratory of Regeneromics, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Lan
authors.initials: L
authors.lastname: Qian
authors.affiliation: Laboratory of Regeneromics, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Gao
authors.affiliation: Laboratory of Regeneromics, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Mingyuan
authors.initials: M
authors.lastname: Wu
authors.affiliation: Laboratory of Regeneromics, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Gao
authors.affiliation: Laboratory of Regeneromics, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Morningside Peking University Joint Laboratory in Integrative Pathobiology, Peking University, Beijing, China.
authors.forename: Gerald L
authors.initials: GL
authors.lastname: Chan
authors.affiliation: Shanghai Municipality Key Laboratory of Veterinary Biotechnology, School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai, China. Electronic address: yanyu@sjtu.edu.cn.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Laboratory of Regeneromics, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China. Electronic address: weihan@sjtu.edu.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Han
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives; D002460:Cell Line; D045744:Cell Line, Tumor; D003106:Colon / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D005472:Fluorouracil / Q000009:adverse effects; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology*; D007375:Interleukin-1 / Q000378:metabolism; D000077146:Irinotecan; D007583:Jejunum / Q000166:cytology / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052016:Mucositis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D020011:Protective Agents / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D000964:Antimetabolites, Antineoplastic; D050759:Cyclin-Dependent Kinase Inhibitor p21; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D020011:Protective Agents; D011994:Recombinant Proteins; D016159:Tumor Suppressor Protein p53; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000077146:Irinotecan; D005472:Fluorouracil; D002166:Camptothecin
keywords: Chemotoxicity; IL-1Ra; Intestinal crypt epithelia; p21(WAF1); p27(KIP1); p53