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

L M Tuyt1, W H Dokter, K Birkenkamp

  • 1Division of Hematology, Department of Medicine, University of Groningen, The Netherlands.

Journal of Immunology (Baltimore, Md. : 1950)
|April 14, 1999
PubMed

Insights

Mitogen-activated protein kinase pathways, including extracellular-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK), activate NF-kappa B transcriptional capacity, driving IL-6 gene expression in human monocytes.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Signaling

Background:

  • Interleukin-6 (IL-6) is a key cytokine involved in immune responses and inflammation.
  • NF-kappa B is a crucial transcription factor regulating the expression of numerous genes, including IL-6.
  • Mitogen-activated protein kinase (MAPK) pathways, such as ERK and JNK, are implicated in cellular signaling.

Purpose of the Study:

  • To investigate the role of ERK1/2 and JNK pathways in IL-6 gene expression in human monocytes.
  • To elucidate the involvement of these MAPK pathways in modulating NF-kappa B activity.
  • To determine the specific mechanisms by which ERK1/2 and JNK influence IL-6 transcription.

Main Methods:

  • Human monocytes were treated with okadaic acid to induce IL-6 secretion.
  • NF-kappa B binding activity, ERK1/2, and JNK phosphorylation/activation were assessed.
  • Specific inhibitors (PD98059) and dominant-negative mutants (Raf-1, JNK1) were used to probe pathway involvement.
  • IL-6 promoter activity and NF-kappa B-mediated transcription were analyzed.

Main Results:

  • Okadaic acid treatment increased IL-6 secretion, NF-kappa B activity, and ERK1/2/JNK activation.
  • Inhibition of the ERK pathway (PD98059) reduced IL-6 secretion.
  • Both ERK and JNK pathways were essential for NF-kappa B-dependent IL-6 promoter activity.
  • The ERK1/2 pathway enhanced NF-kappa B transcriptional activity, not DNA binding.
  • NF-kappa B transcription required serine kinase activity and c-Jun interaction, with JNK potentially phosphorylating c-Jun.

Conclusions:

  • Okadaic acid-induced IL-6 expression is partly mediated by ERK1/2 and JNK pathways activating NF-kappa B transcriptional capacity.
  • The JNK pathway may regulate NF-kappa B-mediated transcription via c-Jun phosphorylation and activation.
  • These findings highlight the intricate crosstalk between MAPK signaling and NF-kappa B in controlling IL-6 production.

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