Induction of a fibrogenic response in mouse colon by overexpression of monocyte chemoattractant protein 1. Issue 5 (18th November 2005)

• Record Type: Journal Article
• Authors: Motomura, Y; Khan, W I; El-Sharkawy, R T; Verma-Gandhu, M; Verdu, E F; Gauldie, J; Collins, S M
• Is Part Of: Gut. Volume 55:Issue 5(2006)
• Page Start: 662
• Page End: 670
• Publication Date: 2005-11-18
• Subjects: CD, Crohn's disease -- ELISA, enzyme linked immunosorbent assay -- IBD, inflammatory bowel disease -- IL, interleukin -- LP, lamina propria -- MCP, monocyte chemoattractant protein -- MM, muscularis mucosa -- MMP, matrix metalloproteinase -- MP, muscularis propria -- SM, submucosa -- SMA, smooth muscle actin -- TGF, transforming growth factor -- TIMP, tissue inhibitor of metalloproteinase -- TNF, tumour necrosis factor; fibrosis -- smooth muscle cell -- fibroblast -- myofibroblast -- T lymphocyte; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gut.2005.068429
• Languages: English
• ISSNs: 0017-5749

Abstract

Abstract : Background and aims: Monocyte chemoattractant protein 1 (MCP-1) is increased transmurally in inflammatory bowel disease (IBD). Although MCP-1 is considered to play an important role in fibrotic disease in other organs, the role of MCP-1 in gut fibrosis is unknown. We investigated the fibrotic potential of MCP-1 in the gut by overexpressing this chemokine in the mouse colorectal wall. Methods: Intramural gene transfer by direct injection of adenovector into the mouse rectal wall was established. C57BL/6 and Rag2 −/− (B and T cell deficient) mice received 2.5×10 9 plaque forming units of an adenovector encoding murine MCP-1 (AdMCP-1) or control virus (AdDL70) via intramural injection. Mice were killed at various time points and tissues were obtained for histopathological and biochemical analysis. Results: AdMCP-1 significantly increased collagen production in the colorectum and this was associated with significant elevation of transforming growth factor β (TGF-β) and tissue inhibitor of metalloproteinase (TIMP-1) protein. Transmural collagen deposition was observed after AdMCP-1 administration, and was accompanied by CD3+ T cells, F4/80+ macrophages, and vimentin+ cell infiltrates. Collagen was differentially distributed, with type I deposited in the muscularis mucosa and muscularis propria and type III in the submucosa and myenteric plexus. AdMCP-1 failed to induce collagen overproduction in immunodeficient Rag2 −/− mice. Conclusion: These findings suggest that MCP-1 can induce fibrosis in the gut and that this process involves interaction between T cells and vimentin positive fibroblasts/myofibroblasts, as well as the subsequent upregulation of TGF-β and TIMP-1 production. This model provides a basis for considering MCP-1 in the pathogenesis of strictures in IBD.