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

LML Tuyt, WHA Dokter, K Birbenkamp, S.B. Koopmans, C Lummen, W Kruijer, E Vellenga*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

134 Citations (Scopus)

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 languageEnglish
Pages (from-to)4893-4902
Number of pages10
JournalJournal of Immunology
Volume162
Issue number8
Publication statusPublished - 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

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