Published online before print May 9, 2002, doi: 10.1161/01.RES.0000021127.83364.7D
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© 2002 American Heart Association, Inc.
Molecular Medicine |
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
From the Center for Cardiovascular Research, University of Rochester, Rochester, NY, and The Scripps Research Institute (J.-D.L.), La Jolla, Calif.
Correspondence to Jun-ichi Abe, MD, PhD, Cardiology Unit, Box 679, 601 Elmwood Ave, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642. E-mail jun-chi_abe{at}urmc.rochester.edu
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-
B 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 NF-B activation by TNF-, we focused on Gab1-dependent signaling. Gab1 inhibited c-Jun and NF-B 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 NF-B transcriptional activation, suggesting a critical role for Gab1 and MEKK3 in TNF- signaling. These data demonstrate that Gab1 and MEKK3 play important roles in endothelial cell inflammation via regulating the activation of c-Jun and NF-B. Furthermore, the IGF-1–mediated downregulation of Gab1 expression represents a novel mechanism to promote vascular inflammation and atherosclerosis.
Key Words: insulin-like growth factor-1 • signal transduction • Grb2-associated binder-1 • tumor necrosis factor-&agr • vascular inflammation
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