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-1β (IL-1β) 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-κB (NF-κB) inhibitor IκB-α was examined by immunoblot analysis.

RESULTS

The IL-1β-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-κB signaling pathways. Tranilast inhibited the IL-1β-induced phosphorylation of the MAPKs extracellular signal-regulated kinase (ERK), p38, and c-Jun NH(2)-terminal kinase (JNK) as well as the phosphorylation and degradation of IκB-α. Tranilast did not exhibit cytotoxicity for corneal fibroblasts.

CONCLUSIONS

Tranilast inhibits the IL-1β-induced production of MMP-1, -2, and -3 by human corneal fibroblasts, with this action likely being mediated through suppression of MAPK and NF-κB 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.