TIMP-1 As a Promising Therapeutic Indicator for the Intestinal Inflammation and Fibrosis

Background: Intestinal fibrosis is a major complication of inflammatory bowel disease (IBD), which can be prevented with anti-inflammatory therapies. However, inflammatory biomarkers do not necessarily reflect the progression of fibrosis, and hence, an indicator that reflects the therapeutic effects of available anti-inflammatory drugs on fibrosis is needed. This study shows that tissue inhibitor of metalloproteinase-1 (TIMP-1) is a potential therapeutic indicator for ongoing intestinal fibrosis in IBD patients.Methods: TIMP-1 mRNA levels in human myofibroblasts were measured, and TIMP-1 expression in the intestine of 10 Crohn’s disease (CD) patients was examined by immunohistochemistry. Colitis was induced in C57BL/6 mice by administration of 1.5% dextran sodium sulfate for 7 days; then, the mice were treated with anti-TNF-α antibody or phosphate-buffered saline for 14 days. Intestinal fibrosis was evaluated by Masson’s trichrome staining, and TIMP-1 mRNA levels in the intestinal tissue and plasma TIMP-1 levels were measured.Results: TIMP-1 expression in human fibroblasts increased after differentiation into myofibroblasts. TIMP-1 expression in CD intestinal tissue was significantly higher in the inflammation area than in the fibrotic or normal areas. In a murine colitis mode in which TIMP-1 mRNA levels were increased, anti-TNF-α antibody administration significantly attenuated inflammation and fibrosis assessed by a reduction in TIMP-1 mRNA levels in intestinal tissue and plasma TIMP-1 levels.Conclusions: The results in this study show that TIMP-1 is a potential new biomarker that could be used to assess the effectivity of different therapeutic strategies for intestinal inflammation and fibrosis in IBD patients.