Persistent activation of nuclear factor-kappaB by interleukin-1beta 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-1beta (IL-1beta) increases the expression of inducible NO synthase (iNOS) in rat vascular smooth muscle cells. IL-1beta 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-1beta-induced early activation but effectively reduced the prolonged activation of NF-kappaB and significantly reduced IL-1beta induction of iNOS. Transfection with antisense, but not sense, phosphorothioate-modified oligodeoxynucleotides directed toward ERK also reduced IL-1beta-induced prolonged NF-kappaB activation and iNOS expression. IkappaBbeta, but not IkappaBalpha degradation, induced by IL-1beta was markedly attenuated when ERK activation was inhibited and could be partially responsible for the persistent NF-kappaB activation. These data suggest that ERK activity is required for persistent NF-kappaB activation by IL-1beta that is necessary for iNOS gene expression.