Anti-fibrogenic effects of the anti-microbial peptide cathelicidin in murine colitis-associated fibrosis.

Autor:	Yoo JH; Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA 90095, USA ; Digestive Disease Center, CHA University Bundang Medical Center, Seongnam 463-712, Republic of Korea., Ho S; Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA 90095, USA., Tran DH; Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA 90095, USA., Cheng M; Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA 90095, USA., Bakirtzi K; Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA 90095, USA., Kukota Y; Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA 90095, USA., Ichikawa R; Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA 90095, USA., Su B; Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA 90095, USA., Tran DH; Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA 90095, USA., Hing TC; Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA 90095, USA., Chang I; Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA 90095, USA., Shih DQ; F. Widjaja Foundation, Inflammatory Bowel & Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA., Issacson RE; Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, MN 55108, USA., Gallo RL; Division of Dermatology, University of California San Diego, San Diego, CA 92093, USA., Fiocchi C; Department of Pathobiology, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA., Pothoulakis C; Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA 90095, USA., Koon HW; Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA 90095, USA.
Jazyk:	angličtina
Zdroj:	Cellular and molecular gastroenterology and hepatology [Cell Mol Gastroenterol Hepatol] 2015 Jan; Vol. 1 (1), pp. 55-74.e1.
DOI:	10.1016/j.jcmgh.2014.08.001
Abstrakt:	Background and 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 (n=6 per group) were administered intracolonically with a trinitrobenzene sulphonic acid (TNBS) enema to induce chronic (6-7 weeks) colitis with fibrosis. mCRAMP peptide (5 mg/kg every 3 day, week 5-7) or cathelicidin gene ( Camp )-expressing lentivirus (10 7 infectious units week 4) were administered intracolonically or intravenously, respectively. 129Sv/J mice were infected with Salmonella typhimurium orally to induce cecal inflammation with fibrosis. Camp expressing lentivirus (10 7 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 to 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-beta1 (TGF-beta1) and/or insulin-like growth factor 1 induced collagen protein and mRNA expression, that was reduced by LL-37 (3-5 µM) through a MAP kinase-dependent mechanism. Conclusion: Cathelicidin can reverse intestinal fibrosis by directly inhibiting collagen synthesis in colonic fibroblasts. Competing Interests: No conflicts of interest exist.
Databáze:	MEDLINE
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