title: Interferon-gamma induces Fas trafficking and sensitization to apoptosis in vascular smooth muscle cells via a PI3K- and Akt-dependent mechanism.
abstract: Vascular smooth muscle cell (VSMC) apoptosis occurs in advanced atherosclerotic plaques where it may contribute to plaque instability. VSMCs express the death receptor Fas but are relatively resistant to Fas-induced apoptosis due in part to the intracellular sequestration of Fas. Although inflammatory cytokines such as interferon (IFN)-gamma present in plaques can prime VSMCs to FasL-induced death, the mechanism of this effect is unclear. We examined Fas expression and FasL-induced apoptosis in human VSMCs in response to IFN-gamma. IFN-gamma induced Fas trafficking to the cell surface within 24 hours, an effect that required Jak2/Stat1 activity. IFN-gamma also stimulated Akt activity, and both Fas trafficking and Stat1 activation were inhibited by blocking PI3K, Akt, or Jak-2. IFN-gamma increased Fas-induced apoptosis in vitro by 46 +/- 8% (mean +/- SEM, P = 0.04), an event that could be abrogated by inhibition of PI3K, Akt, or Jak-2. IFN-gamma also increased Fas-induced apoptosis in vivo 7.5- to 15-fold (P < 0.05) in human arteries transplanted into immunodeficient mice, accompanied by increased Fas and phospho-Ser727-Stat1. We conclude that IFN-gamma primes VSMCs to Fas-induced apoptosis, in part by relocation of Fas to the cell surface, a process that involves PI3K, Akt, and Jak-2/Stat1. IFN-gamma present in plaques may co-operate with FasL to induce VSMC apoptosis in atherosclerosis.
authors.affiliation: Division of Cardiovascular Medicine, University of Cambridge Clinical School of Medicine Addenbrooke's Centre for Clinical Investigation, Box 110, Addenbrooke's Hospital, Cambridge, CB2 2QQ, UK.
authors.forename: Dalya
authors.initials: D
authors.lastname: Rosner
authors.forename: Victoria
authors.initials: V
authors.lastname: Stoneman
authors.forename: Trevor
authors.initials: T
authors.lastname: Littlewood
authors.forename: Nicola
authors.initials: N
authors.lastname: McCarthy
authors.forename: Nichola
authors.initials: N
authors.lastname: Figg
authors.forename: Yinong
authors.initials: Y
authors.lastname: Wang
authors.forename: George
authors.initials: G
authors.lastname: Tellides
authors.forename: Martin
authors.initials: M
authors.lastname: Bennett
mesh_terms: D000818:Animals; D017209:Apoptosis; D050197:Atherosclerosis / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D019014:fas Receptor; D007371:Interferon-gamma; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt