title: The Insect Peptide CopA3 Increases Colonic Epithelial Cell Proliferation and Mucosal Barrier Function to Prevent Inflammatory Responses in the Gut.
abstract: The epithelial cells of the gut form a physical barrier against the luminal contents. The collapse of this barrier causes inflammation, and its therapeutic restoration can protect the gut against inflammation. EGF enhances mucosal barrier function and increases colonocyte proliferation, thereby ameliorating inflammatory responses in the gut. Based on our previous finding that the insect peptide CopA3 promotes neuronal growth, we herein tested whether CopA3 could increase the cell proliferation of colonocytes, enhance mucosal barrier function, and ameliorate gut inflammation. Our results revealed that CopA3 significantly increased epithelial cell proliferation in mouse colonic crypts and also enhanced colonic epithelial barrier function. Moreover, CopA3 treatment ameliorated Clostridium difficile toxin As-induced inflammation responses in the mouse small intestine (acute enteritis) and completely blocked inflammatory responses and subsequent lethality in the dextran sulfate sodium-induced mouse model of chronic colitis. The marked CopA3-induced increase of colonocyte proliferation was found to require rapid protein degradation of p21(Cip1/Waf1), and an in vitro ubiquitination assay revealed that CopA3 directly facilitated ubiquitin ligase activity against p21(Cip1/Waf1). Taken together, our findings indicate that the insect peptide CopA3 prevents gut inflammation by increasing epithelial cell proliferation and mucosal barrier function.
authors.affiliation: From the Department of Life Science, College of Natural Science, Daejin University, Pocheon, Gyeonggido, 487-711, Republic of Korea.
authors.forename: Dae Hong
authors.initials: DH
authors.lastname: Kim
authors.affiliation: the Department of Agricultural Biology, National Academy of Agricultural Science, RDA, Wanju 55365, Republic of Korea.
authors.forename: Jae Sam
authors.initials: JS
authors.lastname: Hwang
authors.affiliation: From the Department of Life Science, College of Natural Science, Daejin University, Pocheon, Gyeonggido, 487-711, Republic of Korea.
authors.forename: Ik Hwan
authors.initials: IH
authors.lastname: Lee
authors.affiliation: From the Department of Life Science, College of Natural Science, Daejin University, Pocheon, Gyeonggido, 487-711, Republic of Korea.
authors.forename: Seung Taek
authors.initials: ST
authors.lastname: Nam
authors.affiliation: From the Department of Life Science, College of Natural Science, Daejin University, Pocheon, Gyeonggido, 487-711, Republic of Korea.
authors.forename: Ji
authors.initials: J
authors.lastname: Hong
authors.affiliation: From the Department of Life Science, College of Natural Science, Daejin University, Pocheon, Gyeonggido, 487-711, Republic of Korea.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.affiliation: From the Department of Life Science, College of Natural Science, Daejin University, Pocheon, Gyeonggido, 487-711, Republic of Korea.
authors.forename: Li Fang
authors.initials: LF
authors.lastname: Lu
authors.affiliation: the Department of Pathology, Daejeon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Daeheung-ro 64, Jung-gu, Daejeon 301-723, Republic of Korea.
authors.forename: Junguee
authors.initials: J
authors.lastname: Lee
authors.affiliation: the Department of Biomedical Engineering, Jungwon University, Goesan, Chungcheongbukdo, 367-700, South Korea.
authors.forename: Heon
authors.initials: H
authors.lastname: Seok
authors.affiliation: the Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90095, and.
authors.forename: Charalabos
authors.initials: C
authors.lastname: Pothoulakis
authors.affiliation: the Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: John Thomas
authors.initials: JT
authors.lastname: Lamont
authors.affiliation: From the Department of Life Science, College of Natural Science, Daejin University, Pocheon, Gyeonggido, 487-711, Republic of Korea, hokim@daejin.ac.kr.
authors.forename: Ho
authors.initials: H
authors.lastname: Kim
mesh_terms: D000818:Animals; D021461:Animals, Outbred Strains; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use*; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects; D001517:Coleoptera / Q000378:metabolism*; D003092:Colitis / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D003106:Colon / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004751:Enteritis / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D005765:Gastrointestinal Agents / Q000494:pharmacology / Q000627:therapeutic use*; D019073:HT29 Cells; D006801:Humans; D019476:Insect Proteins / Q000494:pharmacology / Q000627:therapeutic use*; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D007421:Intestine, Small / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D010539:Permeability / Q000187:drug effects; D034622:RNA Interference; D046509:Tissue Culture Techniques; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D023181:Antimicrobial Cationic Peptides; C583724:CopA3 peptide, Copris tripartitus; D050759:Cyclin-Dependent Kinase Inhibitor p21; D005765:Gastrointestinal Agents; D019476:Insect Proteins; D044767:Ubiquitin-Protein Ligases
keywords: bacterial toxin; cell cycle; cell proliferation; epidermal growth factor (EGF); epithelial cell; inflammation; peptides; proteasome; protein degradation; ubiquitylation (ubiquitination)