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

• Published in: The Journal of immunology (1950) Vol. 162; no. 8; pp. 4893 - 4902
• Main Authors: Tuyt, L M, Dokter, W H, Birkenkamp, K, Koopmans, S B, Lummen, C, Kruijer, W, Vellenga, E
• Format: Journal Article
• Language: English
• Published: United States 15.04.1999
• Subjects: Calcium-Calmodulin-Dependent Protein Kinases - genetics; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Calcium-Calmodulin-Dependent Protein Kinases - physiology; Cells, Cultured; Down-Regulation - genetics; Down-Regulation - immunology; Enzyme Activation - drug effects; Enzyme Activation - immunology; Humans; Interleukin-6 - biosynthesis; Interleukin-6 - genetics; JNK Mitogen-Activated Protein Kinases; Leukemia, Erythroblastic, Acute - genetics; Leukemia, Erythroblastic, Acute - immunology; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Monocytes - drug effects; Monocytes - enzymology; Monocytes - metabolism; Mutagenesis, Site-Directed; NF-kappa B - metabolism; NF-kappa B - physiology; Okadaic Acid - pharmacology; Phosphorylation - drug effects; Promoter Regions, Genetic - drug effects; Promoter Regions, Genetic - immunology; Protein Binding - drug effects; Protein Binding - immunology; Proto-Oncogene Proteins c-jun - physiology; Proto-Oncogene Proteins c-raf - genetics; Transcription, Genetic - drug effects; Transcription, Genetic - immunology; Tumor Cells, Cultured
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.162.8.4893

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-1 or JNK1 showed that both pathways were involved in kappa B-dependent IL-6 promoter activity. By using PD98059, we 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 with 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.