Tumor necrosis factor-alpha regulates insulin-like growth factor-1 and insulin-like growth factor binding protein-3 expression in vascular smooth muscle.
BACKGROUND
Inflammatory mediators such as tumor necrosis factor-alpha (TNF-alpha), interleukin 1beta (IL-1beta), IL-6, and interferon gamma (IFN-gamma) may change coronary plaque integrity by altering vascular smooth muscle cell (VSMC) survival and modifying the extracellular matrix. Insulin-like growth factor-1 (IGF-1) prevents apoptosis, promotes matrix formation, and can decrease TNF-alpha or IL-1beta--induced proteoglycan degradation.


RESULTS
To determine the effects of cytokines on the IGF-1 system, rat aortic VSMCs were exposed to TNF-alpha (10 to 500 ng/mL), IL-1beta (20 pg to 10 ng/mL), IL-6 (100 pg to 15 ng/mL), or IFN-gamma (10 to 600 U/mL). IL-1beta, IL-6, and IFN-gamma did not regulate IGF-1, IGF-1 receptor (R), or IGF binding proteins (IGFBPs). However, TNF-alpha markedly decreased IGF-1 mRNA (85% reduction at 24 hours) and increased IGFBP-3 mRNA and protein (300% increase at 24 hours). These changes were blocked by actinomycin D, consistent with a transcriptional mechanism. Experiments using TNF binding protein-1 indicated that these effects were not attributable to secretion of an autocrine factor. Anti--IGFBP-3 antibodies increased VSMC DNA synthesis 3-fold. In addition, apoptosis induced by TNF-alpha, IFN-gamma, and Fas ligand was markedly reduced by desamino-(1-3)-IGF-1.


CONCLUSIONS
TNF-alpha, a cytokine that is upregulated in atherosclerotic plaques, reduces IGF-1 and increases IGFBP-3 in VSMCs, likely leading to a reduction in bioactive IGF-1. Because IGF-1 is important for growth and survival of VSMCs, its downregulation by TNF-alpha possibly plays a crucial role in acute and chronic coronary syndromes by decreasing VSMC viability and promoting plaque instability.
Anwar
A
A
Division of Cardiology, University Hospital of Geneva, Switzerland.
Zahid
A A
AA
Scheidegger
K J
KJ
Brink
M
M
Delafontaine
P
P
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001161:Arteriosclerosis / Q000209:etiology / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism / Q000494:pharmacology; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004247:DNA / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D053222:Fas Ligand Protein; D015870:Gene Expression / Q000187:drug effects; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000031:analogs & derivatives / Q000235:genetics / Q000378:metabolism*; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology*
D000906:Antibodies; D002352:Carrier Proteins; D017077:Culture Media, Conditioned; D053222:Fas Ligand Protein; C505662:Faslg protein, rat; D018972:Insulin-Like Growth Factor Binding Protein 3; D007375:Interleukin-1; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D019384:Nucleic Acid Synthesis Inhibitors; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha; C069521:recombinant human tumor necrosis factor-binding protein-1; D007334:Insulin-Like Growth Factor I; D007371:Interferon-gamma; D004247:DNA; D017526:Receptor, IGF Type 1