Growth Factors Enhance Interleukin-1β-Induced Persistent Activation of Nuclear Factor-κB in Rat Vascular Smooth Muscle Cells
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Objective— Activation of extracellular signal-regulated kinases (ERKs) is required for interleukin-1β to persistently activate nuclear factor (NF)-κB and concomitantly express inducible NO synthase (iNOS) in rat vascular smooth muscle cells (VSMCs). The present study examined whether platelet-derived growth factor (PDGF) or epidermal growth factor (EGF) could influence the VSMC response to interleukin-1β via an ERK-related signaling pathway.
Methods and Results— Treatment of VSMCs with PDGF or EGF alone potently induced ERK phosphorylation and DNA synthesis but did not induce NF-κB activation or iNOS expression. However, either PDGF or EGF markedly enhanced interleukin-1β-induced persistent NF-κB activation and iNOS expression but did not affect the early and transient NF-κB activation. Growth factor-induced DNA synthesis was attenuated in the presence of interleukin-1β. Inhibition of ERK phosphorylation with selective inhibitors (PD98059 or U0126) attenuated interleukin-1β-induced persistent NF-κB activation and iNOS expression in either the absence or presence of the growth factors.
Conclusions— These results indicate that interleukin-1β-induced expression of NF-κB-dependent genes, such as iNOS, is potentiated in the presence of growth factors through a mechanism requiring ERK-dependent enhanced NF-κB activation, and the results also suggest that NF-κB activation is not required for PDGF or EGF to trigger DNA synthesis in VSMCs.