Tumor Necrosis Factor-α Regulates Insulin-Like Growth Factor-1 and Insulin-Like Growth Factor Binding Protein-3 Expression in Vascular Smooth Muscle

<jats:p> <jats:bold> <jats:italic> <jats:bold> <jats:italic>Background</jats:italic> </jats:bold> — </jats:italic> </jats:bold> 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. </jats:p> <jats:p> <jats:bold> <jats:italic> <jats:bold> <jats:italic>Methods and Results</jats:italic> </jats:bold> — </jats:italic> </jats:bold> 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. </jats:p> <jats:p> <jats:bold> <jats:italic> <jats:bold> <jats:italic>Conclusions</jats:italic> </jats:bold> — </jats:italic> </jats:bold> 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. </jats:p>