Insulin-Like Growth Factor-1 Enhances Inflammatory Responses in Endothelial Cells Role of Gab1 and MEKK3 in TNF- –Induced c-Jun and NF- B Activation and Adhesion Molecule Expression

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 NFB activation by tumor necrosis factor (TNF)and enhanced TNF–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 NFB activation by TNF, we focused on Gab1-dependent signaling. Gab1 inhibited c-Jun and NFB transcriptional activation by TNF. Interestingly, Gab1 inhibited c-Jun transcriptional activity induced by MEKK3 but not MEKK1 and MEK4. Gab1 associated with MEKK3, and a catalytically inactive form of MEKK3 inhibited TNF–induced c-Jun and NFB transcriptional activation, suggesting a critical role for Gab1 and MEKK3 in TNFsignaling. These data demonstrate that Gab1 and MEKK3 play important roles in endothelial cell inflammation via regulating the activation of c-Jun and NFB. Furthermore, the IGF-1– mediated downregulation of Gab1 expression represents a novel mechanism to promote vascular inflammation and atherosclerosis. (Circ Res. 2002;90:1222-1230.)