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
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Research Support, Non-U.S. Gov't
MeSH terms
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Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
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Enzyme Inhibitors / pharmacology
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Flavonoids / pharmacology
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Humans
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Imidazoles / pharmacology
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Interleukin-4 / metabolism*
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Interleukin-4 / pharmacology
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Interleukin-6 / genetics
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Interleukin-6 / metabolism*
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JNK Mitogen-Activated Protein Kinases
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Keratinocytes / drug effects
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Keratinocytes / metabolism*
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MAP Kinase Signaling System
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Mitogen-Activated Protein Kinases / genetics
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Mitogen-Activated Protein Kinases / metabolism
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NF-kappa B / genetics
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NF-kappa B / metabolism
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Pyridines / pharmacology
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Receptors, Interleukin-4 / metabolism
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Regulatory Sequences, Nucleic Acid
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STAT6 Transcription Factor
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Trans-Activators / genetics
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Trans-Activators / metabolism
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Transcription, Genetic
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cdc42 GTP-Binding Protein / metabolism*
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p21-Activated Kinases
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p38 Mitogen-Activated Protein Kinases
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rac1 GTP-Binding Protein / metabolism*
Substances
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Enzyme Inhibitors
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Flavonoids
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Imidazoles
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Interleukin-6
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NF-kappa B
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Pyridines
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Receptors, Interleukin-4
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Recombinant Proteins
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STAT6 Transcription Factor
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STAT6 protein, human
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Trans-Activators
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Interleukin-4
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PAK2 protein, human
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Protein Serine-Threonine Kinases
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p21-Activated Kinases
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Calcium-Calmodulin-Dependent Protein Kinases
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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cdc42 GTP-Binding Protein
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rac1 GTP-Binding Protein
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SB 203580
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one