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 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.
Tuyt
L M
LM
Division of Hematology, Department of Medicine, University of Groningen, The Netherlands.
Dokter
W H
WH
Birkenkamp
K
K
Koopmans
S B
SB
Lummen
C
C
Kruijer
W
W
Vellenga
E
E
D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D048031:JNK Mitogen-Activated Protein Kinases; D004915:Leukemia, Erythroblastic, Acute / Q000235:genetics / Q000276:immunology; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology*; D019319:Okadaic Acid / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000276:immunology; D011485:Protein Binding / Q000187:drug effects / Q000276:immunology; D016755:Proto-Oncogene Proteins c-jun / Q000502:physiology*; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects / Q000276:immunology; D014407:Tumor Cells, Cultured
D015850:Interleukin-6; D016328:NF-kappa B; D016755:Proto-Oncogene Proteins c-jun; D019319:Okadaic Acid; D019908:Proto-Oncogene Proteins c-raf; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases