Inhibition of Interleukin-1β-Induced Matrix Metalloproteinase Expression in Human Corneal Fibroblasts by Tranilast

Purpose: Matrix metalloproteinases (MMPs) mediate the degradation of extracellular matrix proteins and are implicated in the pathogenesis of corneal ulceration. Tranilast, a clinically approved antiallergy drug, has been found to exert various anti-inflammatory effects. We examined the effects of this agent on MMP expression in cultured corneal fibroblasts. Methods: Human corneal fibroblasts were cultured in the absence or presence of interleukin-1 beta (IL-1 beta) or tranilast. The release of MMPs into culture supernatants was assessed by immunoblot analysis and gelatin zymography, and the cellular abundance of MMP mRNAs was determined by reverse transcription and real-time polymerase chain reaction analysis. The phosphorylation of mitogen-activated protein kinases (MAPKs) and the nuclear factor-kappa B (NF-kappa B) inhibitor I kappa B-alpha was examined by immunoblot analysis. Results: The IL-1 beta-induced expression of MMP-1, -2, and -3 in corneal fibroblasts was inhibited by tranilast in a concentration-and time-dependent manner. It was also attenuated by synthetic inhibitors of MAPK or NF-kappa B signaling pathways. Tranilast inhibited the IL-1 beta-induced phosphorylation of the MAPKs extracellular signal-regulated kinase (ERK), p38, and c-Jun NH2-terminal kinase (JNK) as well as the phosphorylation and degradation of I kappa B-alpha. Tranilast did not exhibit cytotoxicity for corneal fibroblasts. Conclusions: Tranilast inhibits the IL-1 beta-induced production of MMP-1, -2, and -3 by human corneal fibroblasts, with this action likely being mediated through suppression of MAPK and NF-kappa B signaling pathways. Tranilast thus warrants further investigation as a potential treatment for corneal ulceration on the basis of its inhibition of MMP expression in corneal fibroblasts.