Persistent activation of nuclear factor-κB by interleukin-1β and subsequent inducible NO synthase expression requires extracellular signal-regulated kinase

The role of extracellular signal-regulated kinase (ERK) was studied in the signaling pathway by which interleukin-1 beta (IL-1 beta) increases the expression of inducible NO synthase (iNOS) in rat vascular smooth muscle cells. IL-1 beta induced a rapid and transient activation of nuclear factor-kappaB (NF-kappaB), followed by a prolonged activation of NF-kappaB that was required to induce iNOS expression. Either PD98059 or U0126, selective inhibitors of ERK activation, did not influence IL-1 beta -induced early activation but effectively reduced the prolonged activation of NF-kappaB and significantly reduced IL-1 beta induction of iNOS. Transfection with antisense, but not sense, phosphorothioate-modified oligodeoxynucleotides directed toward ERK also reduced IL-1 beta -induced prolonged NF-kappaB activation and iNOS expression. I kappaB beta, but not I kappaB alpha degradation, induced by IL-1 beta was markedly attenuated when ERK activation was inhibited and could be partially responsible for the persistent NF-KB activation. These data suggest that ERK activity is required for persistent NF-kappaB activation by IL-1 beta that is necessary for iNOS gene expression.