RGD Reference Report - Tumor necrosis factor-alpha regulates insulin-like growth factor-1 and insulin-like growth factor binding protein-3 expression in vascular smooth muscle. - Rat Genome Database

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Tumor necrosis factor-alpha regulates insulin-like growth factor-1 and insulin-like growth factor binding protein-3 expression in vascular smooth muscle.

Authors: Anwar, A  Zahid, A A  Scheidegger, K J  Brink, M  Delafontaine, P 
Citation: Anwar A, etal., Circulation. 2002 Mar 12;105(10):1220-5. doi: 10.1161/hc1002.105187.
RGD ID: 150340456
Pubmed: PMID:11889017   (View Abstract at PubMed)
DOI: DOI:10.1161/hc1002.105187   (Journal Full-text)


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.
METHODS AND 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.



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Gene Tnf tumor necrosis factor Rattus norvegicus

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