Abstract
In the present study we investigated the possible involvement of the mitogen-activated protein kinase family members extracellular-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK) in mediating IL-6 gene expression in human monocytes, in particular their role in enhancing NF-kappa B activity, Freshly isolated monocytes treated with the protein phosphatase inhibitor okadaic acid secreted high levels of IL-6 protein, which coincided with 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 inhibitor PD98059 inhibited IL-6 secretion from monocytes, Transient overexpression of inactive mutants of either Raf-l or JNK1 showed that both pathways were involved in kappa B-dependent IL-6 promoter activity. By using PD98059,,ve demonstrated that the Raf1/MEK1/ERK1/2 pathway did not affect the DNA 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-mediated gene transcription, both in the context of the IL-6 promoter as well as on its own, was dependent on both serine kinase activity and interaction,vith 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 activation 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.
Original language | English |
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Pages (from-to) | 4893-4902 |
Number of pages | 10 |
Journal | Journal of Immunology |
Volume | 162 |
Issue number | 8 |
Publication status | Published - 15-Apr-1999 |
Keywords
- ACTIVATED PROTEIN-KINASE
- TUMOR-NECROSIS-FACTOR
- DOMINANT-NEGATIVE MUTANT
- RIBOSOMAL S6 KINASE
- TRANSCRIPTION FACTOR
- OKADAIC ACID
- INTERLEUKIN-6 GENE
- SIGNAL-TRANSDUCTION
- BINDING-PROTEINS
- MESSENGER-RNA