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Induction of a fibrogenic response in mouse colon by overexpression of monocyte chemoattractant protein 1

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 2.5×109 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.

  • 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

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