Antifibrogenic Effects of the Antimicrobial Peptide Cathelicidin in Murine Colitis-Associated FibrosisSummary

Jun Hwan Yoo; Samantha Ho; Deanna Hoang-Yen Tran; Michelle Cheng; Kyriaki Bakirtzi; Yuzu Kubota; Ryan Ichikawa; Bowei Su; Diana Hoang-Ngoc Tran; Tressia C. Hing; Irene Chang; David Q. Shih; Richard E. Issacson; Richard L. Gallo; Claudio Fiocchi; Charalabos Pothoulakis; Hon Wai Koon

Cellular and Molecular Gastroenterology and Hepatology (Jan 2015)

Antifibrogenic Effects of the Antimicrobial Peptide Cathelicidin in Murine Colitis-Associated FibrosisSummary

Jun Hwan Yoo,
Samantha Ho,
Deanna Hoang-Yen Tran,
Michelle Cheng,
Kyriaki Bakirtzi,
Yuzu Kubota,
Ryan Ichikawa,
Bowei Su,
Diana Hoang-Ngoc Tran,
Tressia C. Hing,
Irene Chang,
David Q. Shih,
Richard E. Issacson,
Richard L. Gallo,
Claudio Fiocchi,
Charalabos Pothoulakis,
Hon Wai Koon

Affiliations

Jun Hwan Yoo: Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine at the University of CaliforniaâLos Angeles, Los Angeles, California; Digestive Disease Center, CHA University Bundang Medical Center, Seongnam, South Korea
Samantha Ho: Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine at the University of CaliforniaâLos Angeles, Los Angeles, California
Deanna Hoang-Yen Tran: Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine at the University of CaliforniaâLos Angeles, Los Angeles, California
Michelle Cheng: Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine at the University of CaliforniaâLos Angeles, Los Angeles, California
Kyriaki Bakirtzi: Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine at the University of CaliforniaâLos Angeles, Los Angeles, California
Yuzu Kubota: Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine at the University of CaliforniaâLos Angeles, Los Angeles, California
Ryan Ichikawa: Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine at the University of CaliforniaâLos Angeles, Los Angeles, California
Bowei Su: Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine at the University of CaliforniaâLos Angeles, Los Angeles, California
Diana Hoang-Ngoc Tran: Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine at the University of CaliforniaâLos Angeles, Los Angeles, California
Tressia C. Hing: Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine at the University of CaliforniaâLos Angeles, Los Angeles, California
Irene Chang: Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine at the University of CaliforniaâLos Angeles, Los Angeles, California
David Q. Shih: F. Widjaja Foundation, Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California
Richard E. Issacson: Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, Minnesota
Richard L. Gallo: Division of Dermatology, University of CaliforniaâSan Diego, San Diego, California
Claudio Fiocchi: Department of Pathobiology, Cleveland Clinic Foundation, Cleveland, Ohio
Charalabos Pothoulakis: Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine at the University of CaliforniaâLos Angeles, Los Angeles, California
Hon Wai Koon: Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine at the University of CaliforniaâLos Angeles, Los Angeles, California; Correspondence Address correspondence to: Hon Wai Koon, PhD, Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine, MRL Building, Room 1519, 675 Charles E. Young Dr. South, Los Angeles, California 90095. fax: (310) 825-3542.

Journal volume & issue: Vol. 1, no. 1
pp. 55 – 74.e1

Abstract

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Background & Aims: Cathelicidin (LL-37 in human and mCRAMP in mice) represents a family of endogenous antimicrobial peptides with anti-inflammatory effects. LL-37 also suppresses collagen synthesis, an important fibrotic response, in dermal fibroblasts. Here, we determined whether exogenous cathelicidin administration modulates intestinal fibrosis in two animal models of intestinal inflammation and in human colonic fibroblasts. Methods: C57BL/6J mice (nÂ = 6 per group) were administered intracolonically with a trinitrobenzene sulphonic acid (TNBS) enema to induce chronic (6â7 weeks) colitis with fibrosis. We administered mCRAMP peptide (5 mg/kg every 3 day, week 5â7) or cathelicidin gene (Camp)-expressing lentivirus (107 infectious units week 4) intracolonically or intravenously, respectively. We then infected 129Sv/J mice with Salmonella typhimurium orally to induce cecal inflammation with fibrosis. Camp-expressing lentivirus (107 infectious units day 11) was administered intravenously. Results: TNBS-induced chronic colitis was associated with increased colonic collagen (col1a2) mRNA expression. Intracolonic cathelicidin (mCRAMP peptide) administration or intravenous delivery of lentivirus-overexpressing cathelicidin gene significantly reduced colonic col1a2 mRNA expression in TNBS-exposed mice compared with vehicle administration. Salmonella infection also caused increased cecal inflammation associated with collagen (col1a2) mRNA expression that was prevented by intravenous delivery of Camp-expressing lentivirus. Exposure of human primary intestinal fibroblasts and human colonic CCD-18Co fibroblasts to transforming growth factor-Î²1 (TGF-Î²1) and/or insulin-like growth factor 1 induced collagen protein and mRNA expression, which was reduced by LL-37 (3â5 Î¼M) through a MAP kinase-dependent mechanism. Conclusions: Cathelicidin can reverse intestinal fibrosis by directly inhibiting collagen synthesis in colonic fibroblasts. Keywords: Antimicrobial Peptide, Collagen, Inflammatory Bowel Disease

Published in Cellular and Molecular Gastroenterology and Hepatology

ISSN: 2352-345X (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Internal medicine: Specialties of internal medicine: Diseases of the digestive system. Gastroenterology
Website: https://www.journals.elsevier.com/cellular-and-molecular-gastroenterology-and-hepatology/

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