Nutritional factors and resident bacteria participate in the pathogenesis of intestinal inflammation. However, the ways in which bacteria and complex diets might modulate matrix metalloproteinase (MMP) production are unknown. We hypothesized that butyrate might enhance production of MMPs, thus amplifying their response to signals in inflammatory conditions. Human mesenchymal cells were incubated with butyrate and then stimulated with cytokines. MMPs and inhibitors were studied by Western blotting and quantitative RT-PCR. Acetylation of histones was examined in Triton X acetic acid-urea gels by PAGE. We showed that butyrate selectively enhanced the protein production and mRNA expression of stromelysin-1 in tumor necrosis factor-α- or interleukin-1β-stimulated mesenchymal cells. Butyrate alone did not induce any change in MMP production or mRNA expression. It increased the acetylation of histones in mesenchymal cells. Furthermore, acetylation of histones (induced by trichostatin A) reproduced the effects of butyrate. Although butyrate is a major source of nutrient for the colonic epithelial cells, it modulates intestinal inflammation through the secretion of stromelysin-1 in stimulated stromal cells via the inhibition of histone deacetylase.

Background and aims The mechanism by which anti-tumor necrosis factor (TNF)-α therapy promotes rapid closure of fistulas and mucosal wound healing in Crohn's disease (CD) remains unclear. An ex-vivo model of gut T-cell mediated injury indicated that TNF-α blockade prevents tissue damage concomitant with matrix metalloproteinase (MMP) inhibition. We, therefore, hypothesized that the chimeric anti-TNF-α antibody infliximab facilitates wound healing in CD by downregulating tissue degrading MMPs. We focused on MMP-3 (stromelysin-1) and MMP-12 (macrophage metalloelastase) as these two enzymes have been linked to connective tissue destruction in CD. Methods Endoscopic biopsies were taken from 10 CD patients immediately before and after 10 weeks of treatment with infliximab. Before treatment, biopsies were taken from macroscopically inflamed areas, and after treatment were collected from the same locations as before treatment. The degree of mucosal damage was assessed by using a histological scoring system. MMP transcripts were detected by in-situ hybridization on paraffin sections. MMP proteins were determined by immunoblotting on mucosal homogenates. Results Six out of 10 patients had a clinical response to infliximab. MMP-3 and MMP-12 transcripts and proteins, which were highly expressed in CD inflamed mucosa, decreased after treatment in those patients who responded to infliximab. MMP-3 and MMP-12 downregulation was accompanied by a concomitant improvement of the histologic score. No change in MMP expression was found in nonresponders. Conclusion The downregulation of tissue degrading MMPs in CD mucosa may explain the wound repair capacity of infliximab in healing fistulas and ulcers.

Human intestinal lamina propria mesenchymal cells show high surface expression of the α4β1 integrin. Ligation of α4β1 on mesenchymal cell lines with an activating monoclonal anti-α4 antibody or vascular cell adhesion molecule-immunoglobulin (VCAM-IgG) leads to the appearance of activated forms of gelatinase A in culture supernatants, and the de novo expression of activated membrane type-1-matrix metalloproteinase (MT1-MMP). In functional assays, signaling through α4β1 results in an increased capacity of mesenchymal cells to migrate through an artificial extracellular matrix, an effect inhibitable by excess tissue inhibitor of metalloproteinase-2. In organ cultures of human intestine, VCAM-IgG also up-regulates MT1-MMP, and in mucosal ulcers of inflammatory bowel disease patients, MT1-MMP transcripts are abundant, coincident with expression of VCAM-1 on cells at the ulcer margin. Collectively these results suggest that α4β1-induced up-regulation of MT1-MMP may be a crucial factor in the migration of mesenchymal cells into ulcer beds during restitution of diseased gut mucosa.