Matrix metalloproteinase-3 secretion from human colonic subepithelial myofibroblasts: role of interleukin-17

Background. Subepithelial myofibroblasts (SEMFs) play a role in extracellular matrix (ECM) metabolism in the colon. In this study, we investigated the effects of interleukin (IL)-17, IL-1beta, and tumor necrosis factor (TNF)-alpha on matrix metalloproteinase (MMP)-3 secretion in colonic SEMFs. Methods. MMP-3 secretion and MMP-3 mRNA expression were determined by Western and Northern blotting, respectively. The secretion of tissue inhibitor of matrix metalloproteinase (TIMP)-1 was determined by enzyme-linked immunosorbent assay (ELISA). Results. In human colonic SEMFs, MMP-3 secretion and MMP-3 mRNA expression were induced by IL-17, IL-1beta, and TNF-alpha. The effect of IL-17 was observed, but this was weak as compared with those induced by IL-1beta or TNF-alpha. A c-Jun/activating protein-1 (AP-1) inhibitor, curcumin, reduced the IL-17-, IL-1beta-, and TNF-alpha-induced MMP-3 mRNA expression, and mitogen-activated protein (MAP) kinase inhibitors (U0126, PD098059, and SB203580) also blocked MMP-3 secretion. There findings indicate a role for AP-1 and MAP kinases in cytokine-induced MMP-3 secretion. Furthermore, costimulation by IL-17 + IL-1beta and by IL-17 + TNF-alpha induced a marked increase in MMP-3 secretion. The costimulatory effects of these combinations were also observed for TIMP-1 mRNA expression and TIMP-1 secretion. Conclusions. Colonic SEMFs actively secreted MMP-3 in response to IL-17, IL-1beta, and TNF-alpha. This was coupled with TIMP-1 secretion. Colonic SEMFs may play an important role in ECM turnover via MMP secretion.