Abstract

Cathelicidin (LL-37 in human and mCRAMP in mice) is a family of endogenous anti-microbial peptides that protect the host from infection as part of the innate immune response. Recent evidences suggest that cathelicidins may modulate inflammation. Here we determine whether cathelicidin can modulate colonic fibrosis in animal model of colitis as well as human colonic fibroblasts. Wild-type and mCRAMP deficient mice were administered with trinitrobenzene sulphonic acid (TNBS) to induce chronic (7 weeks) colitis. Some mice were treated intracolonically with cathelicidin and colonic histological changes and fibrogenic mediator levels during colonic inflammation were evaluated. TNBS induced chronic colitis associated colonic fibrosis in mice that was reduced by exogenous intracolonic cathelicidin (mCRAMP) administration (5 mg/kg every 3 days). This inhibitory mCRAMP effect was associated with lower colonic histological damage and reduced levels of the fibrotic mediator collagen 1alpha2, fibroblast infiltration and NF-kappaB phosphorylation in colon compared to controls. Moreover, mCRAMP treatment prevented body weight loss due to chronic colitis. Compared to wild-type mice, mCRAMP deficient mice developed more severe TNBS-induced colonic fibrosis. Exposure of human colonic CCD-18Co fibroblasts to LL-37 (5 microM) significantly reduced transforming growth factorbeta1 (50 ng/ml) induced collagen COL1A2 expression as well as NF-kappaB transcriptional activity and p65 phosphorylation. LL-37 treatment did not change basal TGF-beta1 and insulin like growth factor-1 expression in colonic fibroblasts. Suppression of NF-kappaB activity by p65 siRNA further augmented the antifibrogenic effects of LL-37, suggesting that reduced NF-κB activity is involved in the anti-inflammatory effects of LL-37. Cathelicidins are important modulators of colonic fibrosis by mechanisms involving inhibition of NF-κB activity in fibroblasts. Our results also indicate that exogenous cathelicidin administration may represent a novel approach for treatment of colonic fibrosis in inflammatory bowel disease. Supported by a Pilot and Feasibility Study grant from UCLA-CURE Center, Career Development Award from Crohn's and Colitis Foundation of America and K01DK084256 from National Institute of Health to HWK.

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