A MEK inhibitor, PD98059 enhances IL-1-induced NF-κB activation by the enhanced and sustained degradation of IκBα

Interleukin-1 (IL-1) mediates numerous host responses through rapid activation of nuclear factor-κB (NF-κB), but signal pathways leading to the NF-κB activation appear to be complicated and multiplex. We propose a novel regulatory system for NF-κB activation by the extracellular signal-related kinase (ERK) pathway. In a human glioblastoma cell line, T98G, IL-1-induced NF-κB activation was significantly augmented by the pretreatment of a specific MEK inhibitor, PD98059. In contrast, ectopic expression of a constitutive activated form of Raf (v-Raf) reduced IL-1-induced NF-κB activation, and this inhibition was completely reversed by PD98059. Interestingly, PD98059 sustained IL-1-induced NF-κB DNA binding activity by an eletrophoretic mobility shift assay and also IκBα degradation, presumably by augmenting and sustaining the proteasome activation. Concomitantly, two NF-κB dependent genes, A20 and IκBα expression were prolonged with PD98059. These data suggested that MEK-ERK pathway exerts a regulatory effect on NF-κB activation, providing a novel insight on the role of MEK-ERK pathway.