Increased activation of latent TGF-β1 by αVβ3 in human Crohn's disease and fibrosis in TNBS colitis can be prevented by cilengitide

Li, C., Flynn, R. S., Grider, J. R., Murthy, K. S., Kellum, J. M., Akbari, H., & Kuemmerle, J. F.

Inflammatory bowel diseases 19.13 (2013): 2829-2839.

BACKGROUND:

Strictures develop in >30% of patients affected with Crohn's disease. No available medication prevents stricture development in susceptible patients. In Crohn's strictures, but not adjacent normal intestine, TGF-β1 increases in muscularis smooth muscle, increasing collagen I production and strictures. Muscle cells express αVβ3 integrin containing an Arg-Gly-Asp (RGD) binding domain. The aim was to determine whether increased TGF-β1 levels in strictures were the result of latent TGF-β1, which contains an RGD sequence, binding to and activation by αVβ3; and whether cilengitide, which is an RGD-containing αVβ3 integrin inhibitor, decreases TGF-β1 activation and development of fibrosis in chronic 2,4,6 trinitrobenzene sulfonic acid (TNBS)-induced colitis.

DESIGN:

Muscle cells isolated from Crohn's disease strictures and normal resection margin and from the colon of rats after 42 days of chronic TNBS-induced colitis were used to prepare RNA and protein lysates and to initiate primary cultures. The mechanisms leading to increased TGF-β1 activation, collagen I production, and fibrosis were examined in human muscle and in rats. Human cultured cells in vitro and rats in vivo were treated with cilengitide to determines it efficacy to decrease TGF-β1-activation, collagen production, and decrease the development of fibrosis.

RESULTS:

Latent TGF-β1 is activated by the αVβ3 RGD domain in human and rat intestinal smooth muscles. Increased activation of TGF-β1 in Crohn's disease and in TNBS-induced colitis causes increased collagen production, and fibrosis that could be inhibited by cilengitide.

CONCLUSIONS:

Cilengitide, an αVβ3 integrin RGD inhibitor, could be a novel treatment to diminish excess TGF-β1 activation, collagen I production, and development of fibrosis in Crohn's disease.

Increased-activation-of-latent-TGF-1-by-V3-in-human-Crohns-disease-and-fibrosis-in-TNBS-colitis-can-be-prevented-by-cilengitide

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