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

Abstract

Background - Inflammatory mediators such as tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β), IL-6, and interferon γ (IFN-γ) 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-α or IL-1β-induced proteoglycan degradation. Methods and Results - To determine the effects of cytokines on the IGF-1 system, rat aortic VSMCs were exposed to TNF-α (10 to 500 ng/mL), IL-1β (20 pg to 10 ng/mL), IL-6 (100 pg to 15 ng/mL), or IFN-γ (10 to 600 U/mL). IL-1β, IL-6, and IFN-γ did not regulate IGF-1, IGF-1 receptor (R), or IGF binding proteins (IGFBPs). However, TNF-α 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-α, IFN-γ, and Fas ligand was markedly reduced by desamino-(1-3)-IGF-1. Conclusions - TNF-α, 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-α possibly plays a crucial role in acute and chronic coronary syndromes by decreasing VSMC viability and promoting plaque instability.