Inhibition by Tranilast of the Cytokine-Induced Expression of Chemokines and the Adhesion Molecule VCAM-1 in Human Corneal Fibroblasts

Abstract

The synthesis of chemokines and adhesion molecules by corneal fibroblasts contributes to the development of corneal lesions in severe ocular allergy. The effects of the antiallergy drug tranilast on the expression of such molecules were examined in human corneal fibroblasts. The release of chemokines into culture supernatants and the expression of vascular endothelial cell adhesion molecule (VCAM)-1 on the cell surface were determined with enzyme-linked immunosorbent assays. The intracellular abundance of mRNAs was quantitated by reverse transcription and real-time polymerase chain reaction analysis. The phosphorylation of signaling proteins was examined by immunoblot analysis. Tranilast inhibited the release of the chemokines eotaxin-1 and TARC and the surface expression of VCAM-1, induced by the combination of TNF-alpha and IL-4 in corneal fibroblasts. Dexamethasone, but not cyclosporine A or tacrolimus, mimicked these effects of tranilast. Tranilast also inhibited the cytokine-induced upregulation of eotaxin-1 and TARC mRNAs in corneal fibroblasts. Tranilast inhibited the cytokine-induced phosphorylation of the NF-kappaB inhibitor IkappaBalpha and of mitogen-activated protein kinases (ERK, JNK, p38), without affecting that of STAT6, in corneal fibroblasts. Inhibition by tranilast of the cytokine-induced expression of eotaxin-1, TARC, and VCAM-1 in human corneal fibroblasts suggests that this drug might prove effective for treatment of the corneal manifestations of ocular allergic inflammation by targeting corneal fibroblasts directly.