title: Modulation of human monocyte activities by tranilast, SB 252218, a compound demonstrating efficacy in restenosis.
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 E(2) (PGE(2); IC(50) = approximately 1-20 microM), thromboxane B(2) (IC(50) = approximately 10-50 microM), transforming growth factor-beta1 (TGF-beta1; IC(50) = approximately 100-200 microM), and interleukin-8 (IC(50) = approximately 100 microM) 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 leukotriene C(4) or PGE(2) formation was inhibited by tranilast at IC(50) values of 10-40 microM and 2-20 microM, respectively, incubated with or without exogenous arachidonic acid. Interestingly, tranilast (up to 1000 microM) 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 A(2) 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-beta1 was inhibited by tranilast but found to be due in part to inhibition of PGE(2) because exogenous PGE(2) could abrogate tranilast-mediated inhibition of TGF-beta1. 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.
authors.affiliation: SmithKline Beecham Pharmaceuticals, Departments of Immunology, Upper Merion, King of Prussia, Pennsylvania 19406, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Capper
authors.forename: A K
authors.initials: AK
authors.lastname: Roshak
authors.forename: B J
authors.initials: BJ
authors.lastname: Bolognese
authors.forename: P L
authors.initials: PL
authors.lastname: Podolin
authors.forename: T
authors.initials: T
authors.lastname: Smith
authors.forename: D L
authors.initials: DL
authors.lastname: Dewitt
authors.forename: K M
authors.initials: KM
authors.lastname: Anderson
authors.forename: L A
authors.initials: LA
authors.lastname: Marshall
mesh_terms: D016718:Arachidonic Acid / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D003327:Coronary Disease / Q000188:drug therapy*; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000096:biosynthesis / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis; D017997:Leukotriene C4 / Q000096:biosynthesis; D008565:Membrane Proteins; D009000:Monocytes / Q000187:drug effects* / Q000502:physiology; D010741:Phospholipases A / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D062367:ortho-Aminobenzoates / Q000494:pharmacology*
chemical_list: D007527:Isoenzymes; D008565:Membrane Proteins; D016212:Transforming Growth Factor beta; D062367:ortho-Aminobenzoates; D016718:Arachidonic Acid; D017997:Leukotriene C4; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D010741:Phospholipases A; C012293:tranilast; D015232:Dinoprostone; D002118:Calcium