TY - JOUR
T1 - Insulin-like growth factor-1 enhances inflammatory responses in endothelial cells
T2 - Role of Gab1 and MEKK3 in TNF-α-induced c-Jun and NF-κB activation and adhesion molecule expression
AU - Che, Wenyi
AU - Lerner-Marmarosh, Nicole
AU - Huang, Qunhua
AU - Osawa, Masaki
AU - Ohta, Shinsuke
AU - Yoshizumi, Masanori
AU - Glassman, Michael
AU - Lee, Jiing Dwan
AU - Yan, Chen
AU - Berk, Bradford C.
AU - Abe, Jun ichi
PY - 2002/6/14
Y1 - 2002/6/14
N2 - 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 transcriptional activity induced by MEKK3 but not MEKK1 and MEK4. Gab1 associated with MEKK3, and a catalytically inactive form of MEKK3 inhibited TNF-α-induced c-Jun and NF-κB transcriptional activation, suggesting a critical role for Gab1 and MEKK3 in TNF-α signaling. These data demonstrate that Gab1 and MEKK3 play important roles in endothelial cell inflammation via regulating the activation of c-Jun and NF-κB. Furthermore, the IGF-1-mediated downregulation of Gab1 expression represents a novel mechanism to promote vascular inflammation and atherosclerosis.
AB - 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 transcriptional activity induced by MEKK3 but not MEKK1 and MEK4. Gab1 associated with MEKK3, and a catalytically inactive form of MEKK3 inhibited TNF-α-induced c-Jun and NF-κB transcriptional activation, suggesting a critical role for Gab1 and MEKK3 in TNF-α signaling. These data demonstrate that Gab1 and MEKK3 play important roles in endothelial cell inflammation via regulating the activation of c-Jun and NF-κB. Furthermore, the IGF-1-mediated downregulation of Gab1 expression represents a novel mechanism to promote vascular inflammation and atherosclerosis.
KW - Grb2-associated binder-1
KW - Insulin-like growth factor-1
KW - Signal transduction
KW - Tumor necrosis factor-α
KW - Vascular inflammation
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U2 - 10.1161/01.RES.0000021127.83364.7D
DO - 10.1161/01.RES.0000021127.83364.7D
M3 - Article
C2 - 12065326
AN - SCOPUS:0037076787
SN - 0009-7330
VL - 90
SP - 1222
EP - 1230
JO - Circulation research
JF - Circulation research
IS - 11
ER -