TRAIL stimulates proliferation of vascular smooth muscle cells via activation of NF-kappaB and induction of insulin-like growth factor-1 receptor.
TRAIL/Apo2L (tumor necrosis factor-related apoptosis-inducing ligand) is a multifunctional protein regulating homeostasis of the immune system, infection, autoimmune diseases, and apoptosis. However, its function in normal, nontransformed tissues is not clear. Here we show that TRAIL increases vascular smooth muscle cell (VSMC) proliferation in vitro, effects that can be blocked with neutralizing antibodies to TRAIL receptors DR4 and DcR1. In aortocoronary saphenous vein bypass grafts in vivo, TRAIL co-localizes with VSMC, proliferating cell nuclear antigen, and insulin-like growth factor type 1 receptor (IGF1R) expression but not active caspase-3. TRAIL is required for serum-inducible IGF1R expression, and antisense IGF1R inhibits TRAIL-induced VSMC proliferation. At 1 ng/ml, TRAIL stimulates IGF1R mRNA expression greater than insulin-like growth factor-1 and also activates the IGF1R promoter 7-fold. TRAIL-inducible IGF1R expression requires NF-kappaB activation. Consistent with this, ammonium pyrrolidine dithiocarbamate, a pharmacological inhibitor of NF-kappaB, blocks TRAIL-induced IGF1R expression, and p65 overexpression increases IGF1R protein levels. In addition, NF-kappaB binds a novel TRAIL-responsive element on the IGF1R promoter. Our findings suggest that the biological functions of TRAIL in VSMC extend beyond its role in promoting apoptosis. Thus, TRAIL may play an important role in atherosclerosis by regulating IGF1R expression in VSMC in an NF-kappaB-dependent manner.
Kavurma
Mary M
MM
Division of Cardiovascular Medicine, University of Cambridge, Box 110, Addenbrooke's Hospital, Cambridge CB2 2QQ, United Kingdom.
Schoppet
Michael
M
Bobryshev
Yuri V
YV
Khachigian
Levon M
LM
Bennett
Martin R
MR
D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000276:immunology; D001327:Autoimmune Diseases / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000096:biosynthesis / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D001026:Coronary Artery Bypass; D003324:Coronary Artery Disease / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D058851:GPI-Linked Proteins; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D007239:Infections / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009131:Muscle, Smooth, Vascular / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis / Q000276:immunology; D011759:Pyrrolidines / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000276:immunology / Q000378:metabolism*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology / Q000378:metabolism; D053320:Receptors, Tumor Necrosis Factor, Member 10c; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D013859:Thiocarbamates / Q000494:pharmacology; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D019737:Transplants; D053319:Tumor Necrosis Factor Decoy Receptors / Q000276:immunology / Q000378:metabolism
D000975:Antioxidants; D058851:GPI-Linked Proteins; D018809:Proliferating Cell Nuclear Antigen; D011759:Pyrrolidines; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053320:Receptors, Tumor Necrosis Factor, Member 10c; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C108661:TNFRSF10C protein, human; C505653:TNFSF10 protein, human; D013859:Thiocarbamates; D051996:Transcription Factor RelA; D053319:Tumor Necrosis Factor Decoy Receptors; C020972:pyrrolidine dithiocarbamic acid; D017526:Receptor, IGF Type 1; C505407:CASP3 protein, human; D053148:Caspase 3