EP4 receptor regulates collagen type-I, MMP-1, and MMP-3 gene expression in human tendon fibroblasts in response to IL-1β treatment

Tendinopathy is accompanied by inflammation, tendon matrix degradation, or both. Inflammatory cytokine IL-1β, which is a potent inflammatory mediator, is likely present within the tendon. The purpose of this study was to determine the biological impact of IL-1β on tendon fibroblasts by assessing the expression of cPLA2, COX-2, PGE2 and its receptors (EPs), collagen type-I, and MMPs. We also studied the role of the p38 MAPK pathway in IL-1β-induced catabolic effects. We found that IL-1β increased the expression levels of cPLA2 and COX-2, and also increased the secretion of PGE2. Induction of MMPs, such as MMP-1 and MMP-3 at the mRNA level, was also observed after stimulation with IL-1β. Furthermore, the presence of IL-1β significantly decreased the level of collagen type-I mRNA in tendon fibroblasts. These effects were found to be mediated by selective upregulation of EP4 receptor, which is a member of G-protein-coupled receptor that transduces the PGE2 signal. Blocking EP4 receptor by a specific chemical inhibitor abolished IL-1β-induced catabolic effects. These results suggest that IL-1β-induced catabolic action on tendon fibroblasts occurs via the upregulation of two key inflammatory mediators, cPLA2 and COX-2, which are responsible for the synthesis of PGE2. IL-1β further stimulates the expression of EP4 receptor, suggesting positive feedback regulation which may lead to accelerated catabolic processes in tendon fibroblasts. Studies using pathway-specific chemical inhibitors suggest that the p38 MAPK pathway is the key signaling cascade transducing IL-1β-mediated catabolic effects. Collectively, our findings suggest that the EP4 receptor mediates the IL-1β-induced catabolic metabolism via the p38 MAPK pathway in human tendon fibroblasts and may play a major role in the tendon's degenerative changes often seen in the later stages of tendinopathy.