Modulation of human monocyte activities by tranilast, SB 252218, a compound demonstrating efficacy in restenosis

Tranilast (SB 252218) is a compound initially identified as an anti-atopic agent. Recently the compound has demonstrated clear beneficial effects in a nimal models of restenosis. Here we confirm tranilast has broad and profoun d effects on human monocytes, which could contribute to the vascular antifi brotic activity. Tranilast exhibited significant immunomodulatory activity inhibiting endotoxin-induced prostaglandin E-2 (PGE(2); IC50 = similar to1- 20 muM), thromboxane B-2 (IC50 = similar to 10-50 muM), transforming growth factor-beta1 (TGF-beta1; IC50 = similar to 100-200 muM), and interleukin-8 (IC50 = similar to 100 muM) formation, but had no effect on tumor necrosis factor-alpha. Interleukin-12 and -18-induced interferon-gamma formation by monocytes was also attenuated by tranilast. A23187-induced monocyte leukot riene C-4 or PGE(2) formation was inhibited by tranilast at IC50 values of 10-40 sigmaM and 2-20 muM, respectively, incubated with or without exogenou s arachidonic acid. Interestingly, tranilast (up to 1000 muM) had no direct effects on cyclooxygenase I or II activity, nor did it have significant ef fects on human type IIA 14 kDa or type IV 85 kDa phospholipase A(2) activit y. Furthermore, tranilast had no effect on endotoxin-induced cyclooxygenase II protein expression, suggesting tranilast modulates eicosanoid productio n and release by an as yet unidentified mechanism. Alternatively, the expre ssion of TGF-beta1 was inhibited by tranilast but found to be due in part t o inhibition of PGE(2) because exogenous PGE(2) could abrogate tranilast-me diated inhibition of TGF-beta1. Taken together, although a reported direct inhibitor of fibroblast proliferation, we show tranilast also attenuates th e proinflammatory activity of human monocytes, adding to its potential effi cacy as a therapeutic agent in restenosis.