Transforming Growth Factor-β Promotes Pro-fibrotic Behavior by Serosal Fibroblasts via PKC and ERK1/2 Mitogen Activated Protein Kinase Cell Signaling

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Abstract

Objective:

To assess the role of fibroblasts, transforming growth factor (TGF)-β, and cell signal pathways in promoting fibrosis in Crohn's disease (CD).

Summary Background Data:

Intestinal strictures are a major source of morbidity in CD. Fibroblasts found at sites of stricture promote fibrogenesis. The mechanisms underlying this pro-fibrotic behavior remain elusive.

Methods:

Fibroblasts were isolated from strictured and macroscopically normal serosa in patients with CD and from normal serosa in patients with colorectal cancer. Whole cell connective tissue growth factor (CTGF) and fibronectin expression were determined by Western blot analysis. Fibroblast type I collagen expression was evaluated by real-time PCR, while fibroblast contractile activity was measured using fibroblast populated collagen lattices. Cells were stimulated with TGF-β1 and inhibitors of the protein kinase C (PKC) and ERK 1/2 mitogen activated protein (MAP) kinase cell signaling pathways.

Results:

Stricture fibroblasts displayed enhanced constitutive expression of fibronectin. TGF-β promoted fibroblast CTGF, fibronectin, and type I collagen expression and enhanced fibroblast contractile activity. Inhibition of PKC reduced basal collagen expression and contractile activity in Crohn's fibroblasts and attenuated the effect of TGF-β on fibroblast CTGF, fibronectin, and collagen I expression as well as fibroblast contractility. ERK 1/2 inhibition had a similar effect on TGF-β-induced CTGF and fibronectin expression.

Conclusions:

TGF-β is a critical pro-fibrotic growth factor in CD, and its effects are mediated via PKC and ERK 1/2 MAP kinase cell signaling. These pathways may represent novel therapeutic targets for patients with CD characterized by recurrent intestinal stricture formation.

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