Growth factors enhance interleukin-1 beta-induced persistent activation of nuclear factor-kappa B in rat vascular smooth muscle cells

Abstract

Objective: Activation of extracellular signal-regulated kinases (ERKs) is required for interleukin-1beta to persistently activate nuclear factor (NF)-kappaB 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-1beta 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-kappaB activation or iNOS expression. However, either PDGF or EGF markedly enhanced interleukin-1beta-induced persistent NF-kappaB activation and iNOS expression but did not affect the early and transient NF-kappaB activation. Growth factor-induced DNA synthesis was attenuated in the presence of interleukin-1beta. Inhibition of ERK phosphorylation with selective inhibitors (PD98059 or U0126) attenuated interleukin-1beta-induced persistent NF-kappaB activation and iNOS expression in either the absence or presence of the growth factors.

Conclusions: These results indicate that interleukin-1beta-induced expression of NF-kappaB-dependent genes, such as iNOS, is potentiated in the presence of growth factors through a mechanism requiring ERK-dependent enhanced NF-kappaB activation, and the results also suggest that NF-kappaB activation is not required for PDGF or EGF to trigger DNA synthesis in VSMCs.