Induction of a fibrogenic response in mouse colon by overexpression of monocyte chemoattractant protein 1.
OBJECTIVE
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 x 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 beta (TGF-beta) 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.


CONCLUSIONS
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-beta and TIMP-1 production. This model provides a basis for considering MCP-1 in the pathogenesis of strictures in IBD.
Motomura
Y
Y
Intestinal Diseases Research programme, McMaster University, Hamilton, Ontario, Canada. yasumm@gmail.com
Khan
W I
WI
El-Sharkawy
R T
RT
Verma-Gandhu
M
M
Verdu
E F
EF
Gauldie
J
J
Collins
S M
SM
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D018932:Chemokine CCL2 / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D024042:Collagen Type I / Q000032:analysis; D024061:Collagen Type III / Q000032:analysis; D003106:Colon / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005355:Fibrosis; D005822:Genetic Vectors / Q000008:administration & dosage; D006651:Histocytochemistry / Q000379:methods; D007150:Immunohistochemistry / Q000379:methods; D008214:Lymphocytes / Q000502:physiology; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012007:Rectum / Q000737:chemistry; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000032:analysis; D014161:Transduction, Genetic / Q000379:methods; D016212:Transforming Growth Factor beta / Q000032:analysis
D018932:Chemokine CCL2; D024042:Collagen Type I; D024061:Collagen Type III; D019715:Tissue Inhibitor of Metalloproteinase-1; D016212:Transforming Growth Factor beta; D019278:Matrix Metalloproteinase 3