title: Activation of p38-MAPK by CXCL4/CXCR3 axis contributes to p53-dependent intestinal apoptosis initiated by 5-fluorouracil.
abstract: Chemotherapy-induced mucositis (CIM) is a major does limiting side-effect of chemoagents such as 5-fluorouracil (5-FU). Molecules involved in this disease process are still not fully understood. We proposed that the homeostatically regulated genes during CIM may participate in the disease. A cluster of such genes were previously identified by expression gene-array from the mouse jejunum in 5-FU-induced mucositis model. Here, we report that CXCL4 is such a homeostatically regulated gene and serves as a new target for the antibody treatment of CIM. CXCL4 and its receptor CXCR3 were confirmed at both the gene and protein levels to be homeostatically regulated during 5-FU-induced mucositis. Using of CXCL4 neutralizing monoclonal antibody (CXCL4mab) decreased the incidence, severity, and duration of the chemotherapy-induced diarrhea, the major symptom of CIM, in a 5-FU mouse CIM model. Mechanistically, CXCL4mab reduced the apoptosis of the crypt epithelia by suppression of the 5-FU-induced expression of p53 and Bax through its receptor CXCR3. The downstream signaling pathway of CXCL4 in activation of the epithelial apoptosis was identified in an intestinal epithelial cell line (IEC-6). CXCL4 activated the phosphorylation of p38 MAPK, which mediated the stimulated expression of p53 and Bax, and resulted in the ultimate activation of Caspase-8, -9, and -3. Taken together, activation of CXCL4 expression by 5-FU in mice participates in 5-FU-induced intestinal mucositis through upregulation of p53 via activation of p38-MAPK, and CXCL4mab is potentially beneficial in preventing CIM in the intestinal tract.
authors.affiliation: Laboratory of Regeneromics; School of Pharmacy; Shanghai Jiao Tong University; Shanghai, PR China.
authors.forename: Jing
authors.initials: J
authors.lastname: Gao
authors.affiliation: Laboratory of Regeneromics; School of Pharmacy; Shanghai Jiao Tong University; Shanghai, PR China.
authors.forename: Jin
authors.initials: J
authors.lastname: Gao
authors.affiliation: Laboratory of Regeneromics; School of Pharmacy; Shanghai Jiao Tong University; Shanghai, PR China.
authors.forename: Lan
authors.initials: L
authors.lastname: Qian
authors.affiliation: Laboratory of Regeneromics; School of Pharmacy; Shanghai Jiao Tong University; Shanghai, PR China.
authors.forename: Xia
authors.initials: X
authors.lastname: Wang
authors.affiliation: Laboratory of Regeneromics; School of Pharmacy; Shanghai Jiao Tong University; Shanghai, PR China.
authors.forename: Mingyuan
authors.initials: M
authors.lastname: Wu
authors.affiliation: Laboratory of Regeneromics; School of Pharmacy; Shanghai Jiao Tong University; Shanghai, PR China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Laboratory of Regeneromics; School of Pharmacy; Shanghai Jiao Tong University; Shanghai, PR China.
authors.forename: Hao
authors.initials: H
authors.lastname: Ye
authors.affiliation: Shanghai Municipality Key Laboratory of Veterinary Biotechnology; School of Agriculture and Biology; Shanghai Jiao Tong University; Shanghai, PR China.
authors.forename: Shunying
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Shanghai Municipality Key Laboratory of Veterinary Biotechnology; School of Agriculture and Biology; Shanghai Jiao Tong University; Shanghai, PR China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Laboratory of Regeneromics; School of Pharmacy; Shanghai Jiao Tong University; Shanghai, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Han
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects*; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D019743:Chemokines, CXC / Q000378:metabolism*; D003967:Diarrhea / Q000139:chemically induced; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005472:Fluorouracil / Q000009:adverse effects*; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052016:Mucositis / Q000139:chemically induced; D010978:Platelet Factor 4 / Q000378:metabolism*; D051381:Rats; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D057134:Antibodies, Neutralizing; D000964:Antimetabolites, Antineoplastic; D019743:Chemokines, CXC; C577095:Cxcl3 protein, mouse; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D010978:Platelet Factor 4; D048051:p38 Mitogen-Activated Protein Kinases; D020169:Caspases; D005472:Fluorouracil
keywords: CXCL4; apoptosis; chemotherapy; intestinal mucositis; p38; p53