Interferon-gamma induces Fas trafficking and sensitization to apoptosis in vascular smooth muscle cells via a PI3K- and Akt-dependent mechanism.
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.
Rosner
Dalya
D
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.
Stoneman
Victoria
V
Littlewood
Trevor
T
McCarthy
Nicola
N
Figg
Nichola
N
Wang
Yinong
Y
Tellides
George
G
Bennett
Martin
M
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*
D019014:fas Receptor; D007371:Interferon-gamma; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt