From the AGA Journals

Cathelicidins might help prevent, treat colonic fibrosis

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Cathelicidins may be a powerful therapy for intestinal fibrosis

Fibrosis is a major complication of Crohn’s disease that can lead to strictures and intestinal obstruction. While biologic therapies have revolutionized medical treatment of Crohn’s disease and may reduce the incidence of recurrent stricturing disease, as many as 20% of Crohn’s disease patients treated with these agents still develop strictures.

One attractive therapeutic target could be TGF-beta, which induces fibroblasts to synthesize collagen and is upregulated in Crohn’s disease strictures. Unfortunately, anti-TGF-beta1 antibody therapy failed to work in other fibrotic diseases. In addition, toxicity might be expected in Crohn’s disease, as TGF-beta has pleiotropic functions in the gut, some of which are critical to homeostasis.

Recent work in extraintestinal organs has elucidated the involvement of cathelicidins, antimicrobial cationic peptides, in fibrosis. For example, LL-37, the cleaved form of human cathelicidin, can reduce TGF-beta–induced collagen synthesis by human keloid fibroblasts. However, the ability of cathelicidins to limit intestinal fibrosis has not been explored.

The study by Yoo et al. is important because it demonstrates that cathelicidins may be a powerful therapy for intestinal fibrosis. Importantly, cathelicidin therapy does not appear to affect TGF-beta signaling, as LL-37 therapy did not affect TGF-beta1 expression in vivo, but did inhibit TGF-beta–induced collagen production by primary Crohn’s disease intestinal fibroblasts in vitro.

It is also important to recognize that cathelicidins are already being developed as therapy to limit fibrosis in extra-intestinal diseases. Thus, much in the same way Crohn’s disease patients benefited from the development of anti-TNF-beta biologics for rheumatoid arthritis, it may be possible to take advantage of ongoing studies to reduce the cost and time involved in delivering a new therapeutic agent to patients.

Dr. Stefania Vetrano is a research associate at the IBD Center, Humanitas Clinical and Research Center, Rozzano, Milan. She has no conflicts of interest.


 

References

Peptides known as cathelicidins directly inhibited collagen synthesis in human colonic fibroblasts and in mice with colitis, authors of a controlled, prospective study reported. The findings appeared Nov. 11 in Cellular and Molecular Gastroenterology and Hepatology.

“Our results strongly suggest that cathelicidin administration may be a novel approach to prevent or treat inflammatory bowel disease and IBD-related colonic fibrosis,” said Dr. Jun Hwan Yoo at the University of California, Los Angeles, and his associates.

Cathelicidins are endogenous antimicrobial peptides that exhibit “potent” anti-inflammatory effects against acute colitis, and inhibit colonic fibrosis in mice with chronic or infectious colitis, the investigators said. In past studies, cathelicidin-deficient mice were more susceptible to infections, had poorer wound healing, and developed worse colitis, compared with mice that were not cathelicidin deficient, they added. Cathelicidins also inhibit collagen synthesis in human dermal fibroblasts, they said (Cellular and Molecular Gastroenterology and Hepatology 2014 Nov. 11 10.1016/j.jcmgh.2014.08.001 [doi:10.1016/j.jcmgh.2014.08.001]).

To further explore the role of cathelicidins in intestinal fibrosis, Dr. Yoo and associates created two murine models of intestinal inflammation by infecting mice with Salmonella or by administering trinitrobenzene sulfonic acid enemas. Then they administered either intracolonic mCRAMP peptide at a dose of 5 mg/kg every 3 days, or intravenous injections of a lentivirus that overexpressed the cathelicidin gene. The researchers also exposed human intestinal fibroblasts and human colonic CCD-18Co fibroblasts to transforming growth factor beta1 (TGF-beta1) or to insulinlike growth factor 1, which induced collagen protein and mRNA expression that mimicked intestinal fibrosis. Then they exposed these cells to 3-5 mcm of the human cathelicidin LL-37.

The groups of mice with colitis had significantly higher colonic expression of collagen mRNA and significantly more colon tissue damage than did the normal controls, said the researchers. Mice with colitis that received mCRAMP or lentivirus-overexpressing cathelicidin gene had significantly lower collagen mRNA levels and less cecal and colonic collagen deposition, compared with mice that received only the vehicle control, they added (all P values less than .05). Intracolonic mCRAMP also restored body weight (P = .0178) in mice with colitis, compared with untreated controls, they added. Furthermore, LL-37 inhibited collagen synthesis in human intestinal and colonic fibroblasts (P = .0001), they said.

The research was supported by the UCLA CURE Center, the Crohn’s and Colitis Foundation of America, the National Institutes of Health, the Blinder Research Foundation for Crohn’s Disease, the Eli and Edythe Broad Chair, and the U.S. Public Health Service. The authors declared no conflicts of interest.

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