IL-4 regulation of IL-6 production involves Rac/Cdc42- and p38 MAPK-dependent pathways in keratinocytes

Oncogene. 2000 Mar 16;19(12):1596-604. doi: 10.1038/sj.onc.1203458.

Abstract

The stress-activated pathways leading to activation of p38 MAP kinase (p38 MAPK) and c-jun N-terminal kinases (JNK) have been shown to be activated by pro-inflammatory cytokines, physical and chemical stresses as well as a variety of hematopoietic growth factors. One exception is interleukin (IL)-4, which does not activate this pathway in hematopoietic cell. We report here that in A431, a keratinocytic cell line, IL-4 activates Rac and Cdc42 and their downstream effector p21-activated kinase (PAK). Rac and Cdc42 appear to regulate a protein kinase cascade initiated at the level of PAK and leading to activation of p38 MAPK, since IL-4 stimulates tyrosine phosphorylation of p38 MAPK and increases its catalytic activity. As A431 cells are able to produce IL-6 in response to IL-4 stimulation, we assessed the involvement of p38 MAPK in IL-6 gene expression. A pyrimidazole compound, SB203580, a specific inhibitor of p38 MAPK, inhibits production and gene expression of IL-6. SB203580 reduced significantly the stability of IL-6 mRNA. Here we provide evidence that p38 MAPK is activated in response to IL-4 and is involved in IL-6 synthesis by stabilizing IL-6 mRNA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Enzyme Inhibitors / pharmacology
  • Flavonoids / pharmacology
  • Humans
  • Imidazoles / pharmacology
  • Interleukin-4 / metabolism*
  • Interleukin-4 / pharmacology
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism*
  • JNK Mitogen-Activated Protein Kinases
  • Keratinocytes / drug effects
  • Keratinocytes / metabolism*
  • MAP Kinase Signaling System
  • Mitogen-Activated Protein Kinases / genetics
  • Mitogen-Activated Protein Kinases / metabolism
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Pyridines / pharmacology
  • Receptors, Interleukin-4 / metabolism
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Regulatory Sequences, Nucleic Acid
  • STAT6 Transcription Factor
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transcription, Genetic
  • cdc42 GTP-Binding Protein / metabolism*
  • p21-Activated Kinases
  • p38 Mitogen-Activated Protein Kinases
  • rac1 GTP-Binding Protein / metabolism*

Substances

  • Enzyme Inhibitors
  • Flavonoids
  • Imidazoles
  • Interleukin-6
  • NF-kappa B
  • Pyridines
  • Receptors, Interleukin-4
  • Recombinant Proteins
  • STAT6 Transcription Factor
  • STAT6 protein, human
  • Trans-Activators
  • Interleukin-4
  • PAK2 protein, human
  • Protein Serine-Threonine Kinases
  • p21-Activated Kinases
  • Calcium-Calmodulin-Dependent Protein Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • cdc42 GTP-Binding Protein
  • rac1 GTP-Binding Protein
  • SB 203580
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one