Effect of interleukin-1 receptor antagonist on vascular smooth muscle cell proliferation

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      The development of the atheromatous plaque is largely dependent on vascular smooth muscle cell proliferation and production of biologically active compounds such as cytokines and growth factors. Cytokines such as IL-1 derived from blood vessel wall may contribute to regional defense or pathology. Neutralization of the effects mediated by IL-1 by a receptor antagonist specific for IL-1α and IL-1β has been shown to reduce the possible pathologic consequences induced by IL-1 in the regional environment. The effect of human recombinant interleukin-1 receptor antagonist (hrIL-1ra), a new member of the IL-1 family, has been assessed on modulating vascular smooth muscle cell (VSMC) proliferation in the rat. A significant dose- and time-dependent reduction of DNA synthesis was observed when hrIL-Ira was added to the cell cultures. The maximum inhibitory effect was seen using IL-Ira at a concentration of 250 ng/ml and after 48 h incubation with cultured vascular smooth muscle cells. Furthermore, hrIL-Ira inhibited VSMC growth in the presence of exogenous mitogenic doses of IL-Iα. The addition of indomethacin to the cultures did not modify the inhibitory events. These data suggest a possible pharmacologic role for IL-1ra in inhibiting VSMC proliferation by possibly interfering with the autocrine regulatory pathway of IL-1.



      Ab (antibody), FCS (fetal calf serum), hr (human recombinant), IL-1 (interleukin-1), IL-1ra (interleukin-1 receptor antagonist), LPS (lipopolysaccharide), VSMC (vascular smooth muscle cell)
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        • Hansson G.K.
        • Jonasson L.
        • Seifert P.S.
        • Stemme S.
        Immune mechanism in atherosclerosis.
        Arteriosclerosis. 1989; 9: 567
        • Munro J.M.
        • Cotran R.
        The pathogenesis of atherosclerosis: atherogenesis and inflammation.
        Lab. Invest. 1988; 58: 249
        • Ross R.
        The pathogenesis of atherosclerosis: an update.
        N. Engl. J. Med. 1986; 314: 488
        • Libby P.
        • Warner S.J.C.
        • Friedman G.B.
        Interleukin 1: a mitogen for human vascular smooth muscle cells that induces the release of growth-inhibitory prostanoids.
        J. Clin. Invest. 1988; 81: 487
        • Faggiotto A.
        • Ross R.
        • Harker L.
        Studies of hypercholesterolemia in the nonhuman primate. I. Changes that lead to fatty streak formation.
        Arteriosclerosis. 1984; 4: 323
        • Libby P.
        • Ordovas J.M.
        • Birinyi L.K.
        • Auger K.R.
        • Dinarello C.A.
        Inducible interleukin-1 gene expression in human vascular smooth muscle cells.
        J. Clin. Invest. 1986; 78: 1432
        • Warner S.J.C.
        • Auger K.R.
        • Libby P.
        Human interleukin-1 induces interleukin-1 gene expression in human vascular smooth muscle cells.
        J. Exp. Med. 1981; 165: 1316
        • Clinton S.K.
        • Fleet J.C.
        • Harald L.
        • Salomon R.N.
        • Clark B.D.
        • Cannon J.G.
        • Shaw A.R.
        • Dinarefo C.A.
        • Libby P.
        Interleukin 1 gene expression in rabbit vascular tissue in vivo.
        Am. J. Pathol. 1991; 138: 1005
        • Raines E.W.
        • Dower S.K.
        • Ross R.
        Interleukin-1 mitogenic activity for fibroblasts and smooth muscle cells is due to PDGF-AA.
        Science. 1989; 243: 393
        • Moyer C.F.
        • Sajuthi D.
        • Tulli H.
        • Williams J.K.
        Synthesis of IL-1 alpha and IL-1 beta by arterial cells in atherosclerosis.
        Am. J. Pathol. 1991; 138: 951
        • Polverini P.J.
        • Cotran R.S.
        • Sholley M.M.
        Endothelial proliferation in the delayed hypersensitivity reaction: an autoradiographic study.
        J. Immunol. 1977; 118: 529
        • Bevilacqua M.P.
        • Pober J.S.
        • Majeau G.R.
        • Cotran R.S.
        • Gimbrone Jr., M.A.
        Interleukin-1 induces biosynthesis and cell surface expression of procoagulant activity in human vascular endothelial cells.
        J. Exp. Med. 1984; 160: 618
        • Bevilacqua M.P.
        • Pober J.S.
        • Wheeler M.E.
        • Mendrick D.
        • Cotran R.S.
        • Gimbrone Jr., M.A.
        Interleukin-1 acts on cultured vascular endothelial cells to increase the adhesion of polymorphonuclear leukocytes, monocytes and related leukocyte cell line.
        J. Clin. Invest. 1985; 76: 2003
        • Conti P.
        • Reale M.
        • Fiore S.
        • Cancelli A.
        • Angeletti P.U.
        • Dinarello C.A.
        Recombinant interleukin-1 and tumor necrosis factor acting in synergy to release throm boxane, 6-keto-PGFla and PGE2 by human neutrophils.
        Scand. J. Rheumatol. 1988; 17: 318
        • Okusawa S.
        • Gelfand J.A.
        • Ikejima T.
        • Connolly R.S.
        • Dinarello C.A.
        Interleukin-1 induces a shock-like state in rabbits. Synergism with tumor necrosis factor and the effect of a cyclooxygenase inhibitor.
        J. Clin. Invest. 1988; 81: 1162
        • Dinarello C.A.
        • Conti P.
        • Mier J.W.
        Effects of human interleukin-1 on natural killer cell activity: is fever a host defence mechanism for tumor killing?.
        Yale J. Biol. Med. 1986; 59: 9
        • Eisenberg S.P.
        • Evans R.J.
        • Arend W.P.
        • Verderber E.
        • Brewer M.T.
        • Hannum C.H.
        • Thompson R.C.
        Primary structure and functional expression from cDNA of a human interleukin-1 receptor antagonist.
        Nature. 1990; 343: 341
        • Mazzei G.J.
        • Seckinger P.L.
        • Dayer J.M.
        • Shaw A.R.
        Purification and characterization of a 26 kDa competitive inhibitor of interleukin-1.
        Eur. J. Immunol. 1990; 20: 683
        • Dinarello C.A.
        Interleukin-1 and interleukin-1 antagonism.
        Blood. 1991; 77: 1627
        • Arend W.P.
        • Welgus H.G.
        • Thompson R.C.
        • Eisenberg S.P.
        Biological properties of recombinant human monocyte-derived interleukin-1 receptor antagonist.
        J. Clin. Invest. 1990; 85: 1694
        • Vergara-Dauten M.
        • Balconi G.
        • Breviario F.
        • Chiabrando C.
        • deGaetano G.
        • Dejana E.
        Further studies on the mechanism of action of human plasma in stimulating prostacyclin production by rat smooth muscle cells.
        Thromb. Hemost. 1985; 53: 372
        • Rossenwasser L.J.
        • Dinarello C.A.
        Ability of human leukocytic pyrogen to enhanced phytohemoaglutinin induced murine thymocyte proliferation.
        Cell. Immunol. 1981; 163: 134
        • Conti P.
        • Reale M.
        • Angeletti P.U.
        • Dinarello C.A.
        Restoration of anti-interleukin-I depressed natural killer activity by human recombinant interferon alpha or gamma, human recombinant interleukin-2 and indomethacin.
        Int. J. Immunopharmacol. 1988; 10: 907
        • Dinarello C.A.
        • Thompson R.C.
        Blocking IL-1 receptor antagonist in vivo and in vitro.
        Immunol. Today. 1991; 12: 404
        • Arend W.P.
        Interleukin-1 receptor antagonist. A new member of the interleukin-1 family.
        J. Clin. Invest. 1991; 88: 1445
        • Granowitz E.V.
        • Clark B.D.
        • Mancillo J.
        • Dinarello C.A.
        Interleukin-1 receptor antagonist competitively inhibits the binding of interleukin-1 to the type II interleukin-1 receptor.
        J. Biol. Chem. 1991; 266: 14147
        • Granowitz E.V.
        • Pontsiaka D.D.
        • Dinarello C.A.
        Production of interleukin-1 receptor antagonist during experimental endotoxemia.
        Lancet. 1991; 338: 1423
        • Wakabayashi G.
        • Gelfand J.A.
        • Burke J.F.
        • Thompson R.C.
        • Dinarello C.A.
        A specific receptor antagonist for interleukin-1 prevents Escherichia coli-induced shock in rabbits.
        FASEB J. 1991; 5: 338
        • Ohlsson K.
        • Biork P.
        • Bergenfeld M.
        • Hageman R.
        • Thompson R.C.
        Interleukin-1 receptor antagonist reduces mortality from endotoxin shock.
        Nature. 1990; 348: 550
        • Arend W.P.
        • Joselin F.G.
        • Thompson R.C.
        • Hannum C.H.
        An IL-1 inhibitor from human monocytes, Production and characterization of biologic properties.
        J. Immunol. 1989; 143: 1851
        • McIntyre K.W.
        • Stepan G.J.
        • Kolinsky D.K.
        • Benjamin W.R.
        • Plocinski J.M.
        • Kaffka K.L.
        • Campen C.A.
        • Chizzonite R.A.
        • Kilian P.L.
        Inhibition of Interleukin-1 (IL-1) binding and bioactivity in vitro and modulation of acute inflammation in vivo by IL-1 receptor antagonist and anti-IL-l-receptor monoclonal antibody.
        J. Exp. Med. 1991; 173: 931
        • Ip J.H.
        • Fuster V.
        • Badimon L.
        • Badimon J.
        • Taubman M.B.
        • Cheseboro J.H.
        Syndromes of accelerated atherosclerosis: role of vascular injury and smooth muscle cell proliferation.
        JACC. 1990; 15: 1667
        • Loppnow H.
        • Libby P.
        Functional significance of human vascular smooth muscle cell-derived interleukin-1 in paracrine and autocrine regulation pathways.
        Exp. Cell Res. 1992; 198: 283