Extracellular-regulated kinase 1/2, Jun N-terminal kinase, and c-Jun are involved in NF-kappa B-dependent IL-6 expression in human monocytes

In the present study we investigated the possible involvement of the mitoge n-activated protein kinase family members extracellular-regulated kinase 1/ 2 (ERK1/2) and c-Jun N-terminal kinase (JNK) in mediating IL-6 gene express ion in human monocytes, in particular their role in enhancing NF-kappa B ac tivity, Freshly isolated monocytes treated with the protein phosphatase inh ibitor okadaic acid secreted high levels of IL-6 protein, which coincided w ith enhanced binding activity of NF-kappa B as well as with phosphorylation and activation of the ERK1/2 and JNK proteins. The ERK pathway-specific in hibitor PD98059 inhibited IL-6 secretion from monocytes, Transient overexpr ession of inactive mutants of either Raf-l or JNK1 showed that both pathway s were involved in kappa B-dependent IL-6 promoter activity. By using PD980 59,,ve demonstrated that the Raf1/MEK1/ERK1/2 pathway did not affect the DN A binding of NF-kappa B but, rather, acted at the level of transcriptional activity of NF-kappa B. Interestingly, it was shown that NF-kappa B-mediate d gene transcription, both in the context of the IL-6 promoter as well as o n its own, was dependent on both serine kinase activity and interaction,vit h c-Jun protein. We conclude that okadaic acid-induced IL-6 gene expression is at least partly mediated through the ERK1/2 and JNK pathway-dependent a ctivation of NF-kappa B transcriptional capacity. Our results suggest that the JNK pathway may regulate NF-kappa B-mediated gene transcription through its phosphorylation and activation of c-Jun.