Anti-fibrogenic effects of the anti-microbial peptide cathelicidin in murine colitis-associated fibrosis.
OBJECTIVE
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 (107infectious units week 4) were administered intracolonically or intravenously, respectively. 129Sv/J mice were infected withSalmonella typhimuriumorally to induce cecal inflammation with fibrosis.Campexpressing lentivirus (107infectious 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.Salmonellainfection also caused increased cecal inflammation associated with collagen (col1a2) mRNA expression that was prevented by intravenous delivery ofCamp-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.


CONCLUSIONS
Cathelicidin can reverse intestinal fibrosis by directly inhibiting collagen synthesis in colonic fibroblasts.
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.
Jun Hwan
JH
Yoo
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.
Samantha
S
Ho
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.
Deanna Hoang-Yen
DH
Tran
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.
Michelle
M
Cheng
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.
Kyriaki
K
Bakirtzi
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.
Yuzu
Y
Kukota
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.
Ryan
R
Ichikawa
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.
Bowei
B
Su
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.
Diana Hoang-Ngoc
DH
Tran
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.
Tressia C
TC
Hing
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.
Irene
I
Chang
F. Widjaja Foundation, Inflammatory Bowel & Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
David Q
DQ
Shih
Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, MN 55108, USA.
Richard E
RE
Issacson
Division of Dermatology, University of California San Diego, San Diego, CA 92093, USA.
Richard L
RL
Gallo
Department of Pathobiology, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Claudio
C
Fiocchi
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.
Charalabos
C
Pothoulakis
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.
Hon Wai
HW
Koon
Anti-microbial peptide; collagen; inflammatory bowel disease