Tumor necrosis factor-alpha promotes macrophage-induced vascular smooth muscle cell apoptosis by direct and autocrine mechanisms.
OBJECTIVE
We have previously shown that human macrophages induce human plaque vascular smooth muscle cell (VSMC) apoptosis by cell-cell proximity, Fas-L, and nitric oxide (NO), thereby predisposing to plaque rupture. This study sought to analyze whether tumor necrosis factor-alpha (TNF-alpha) contributes additionally to macrophage-induced VSMC apoptosis.


RESULTS
Macrophage-induced VSMC apoptosis was examined in direct coculture. Antagonistic antibodies to TNF-receptor (R1) inhibited VSMC apoptosis, and preincubation of monocytes and VSMCs indicated that TNF-R1 on both cell types contributed to macrophage-induced VSMC apoptosis. Correspondingly, both monocytes and VSMCs expressed TNF-R1, and macrophages expressed cell surface TNF-alpha. Two NO donors upregulated VSMC surface TNF-R1, and exogenous TNF-alpha induced VSMC apoptosis synergistically with the NO donor diethylenetriamine/NO, indicating that NO sensitizes VSMCs to TNF-alpha. Neutralizing anti-TNF-R1 antibodies inhibited macrophage activation assessed by Fas-L expression and NO secretion.


CONCLUSIONS
TNF-alpha promotes macrophage-induced VSMC apoptosis by autocrine and direct pathways.
Boyle
Joseph J
JJ
Unit of Cardiovascular Medicine, Addenbrooke's Hospital, Cambridge, UK. joseph.boyle@ic.ac.uk
Weissberg
Peter L
PL
Bennett
Martin R
MR
D019138:Antibodies, Blocking / Q000494:pharmacology; D015703:Antigens, CD / Q000096:biosynthesis / Q000276:immunology; D000954:Antigens, Surface / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001161:Arteriosclerosis / Q000378:metabolism / Q000473:pathology; D002339:Carotid Arteries / Q000737:chemistry / Q000473:pathology; D002460:Cell Line; D002478:Cells, Cultured; D053222:Fas Ligand Protein; D006801:Humans; D042541:Intracellular Space / Q000737:chemistry; D008074:Lipoproteins / Q000502:physiology; D008262:Macrophage Activation / Q000502:physiology; D008264:Macrophages / Q000737:chemistry / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D009000:Monocytes / Q000737:chemistry; D009131:Muscle, Smooth, Vascular / Q000737:chemistry / Q000166:cytology* / Q000187:drug effects / Q000473:pathology; D009569:Nitric Oxide / Q000096:biosynthesis; D020030:Nitric Oxide Donors / Q000494:pharmacology; D011073:Polyamines / Q000494:pharmacology; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D012422:Rupture, Spontaneous / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects; D019014:fas Receptor / Q000378:metabolism / Q000502:physiology
D019138:Antibodies, Blocking; D015703:Antigens, CD; D000954:Antigens, Surface; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008074:Lipoproteins; D008562:Membrane Glycoproteins; D020030:Nitric Oxide Donors; D011073:Polyamines; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; C005391:diethylenetriamine; D009569:Nitric Oxide