Insulin-Like Growth Factor-1 Enhances Inflammatory Responses in Endothelial Cells

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Abstract
Insulin-like growth factor (IGF)-1 and the type I IGF-1 receptor are important regulators of vascular function that may contribute to cardiovascular disease. We hypothesized that IGF-1 causes endothelial cell dysfunction and expression of neutrophil and monocyte adhesion molecules by enhancing pro-inflammatory cytokine signal transduction. Long-term IGF-1 treatment of endothelial cells potentiated c-Jun and nuclear factor NF-κB activation by tumor necrosis factor (TNF)-α and enhanced TNF-α–mediated adhesion molecule expression. In response to IGF-1 treatment, the expression of kinases in the c-Jun/c-Jun NH2-terminal kinase signaling pathway (MEKK1, MEK4, and JNK1/2) was unchanged, but expressions of insulin receptor substrate-1 and Grb2-associated binder-1 (Gab1) were significantly decreased. Because Gab1 is involved in both c-Jun and NF-κB activation by TNF-α, we focused on Gab1-dependent signaling. Gab1 inhibited c-Jun and NF-κB transcriptional activation by TNF-α. Interestingly, Gab1 inhibited c-Jun tr...