Abstract

Tranilast (SB 252218) is a compound initially identified as an anti-atopic agent. Recently the compound has demonstrated clear beneficial effects in animal models of restenosis. Here we confirm tranilast has broad and profound effects on human monocytes, which could contribute to the vascular antifibrotic activity. Tranilast exhibited significant immunomodulatory activity inhibiting endotoxin-induced prostaglandin E₂ (PGE₂; IC₅₀ = ∼1–20 μM), thromboxane B₂(IC₅₀ = ∼10–50 μM), transforming growth factor-β1 (TGF-β1; IC₅₀ = ∼100–200 μM), and interleukin-8 (IC₅₀ = ∼100 μM) formation, but had no effect on tumor necrosis factor-α. Interleukin-12 and -18-induced interferon-γ formation by monocytes was also attenuated by tranilast. A23187-induced monocyte leukotriene C₄ or PGE₂formation was inhibited by tranilast at IC₅₀ values of 10–40 μM and 2–20 μM, respectively, incubated with or without exogenous arachidonic acid. Interestingly, tranilast (up to 1000 μM) had no direct effects on cyclooxygenase I or II activity, nor did it have significant effects on human type IIA 14 kDa or type IV 85 kDa phospholipase A₂ activity. Furthermore, tranilast had no effect on endotoxin-induced cyclooxygenase II protein expression, suggesting tranilast modulates eicosanoid production and release by an as yet unidentified mechanism. Alternatively, the expression of TGF-β1 was inhibited by tranilast but found to be due in part to inhibition of PGE₂ because exogenous PGE₂ could abrogate tranilast-mediated inhibition of TGF-β1. Taken together, although a reported direct inhibitor of fibroblast proliferation, we show tranilast also attenuates the proinflammatory activity of human monocytes, adding to its potential efficacy as a therapeutic agent in restenosis.