Regulation of interleukin-1beta-induced interleukin-6 gene expression in human fibroblast-like synoviocytes by p38 mitogen-activated protein kinase.
Involvement of p38 mitogen-activated protein (MAP) kinase in interleukin (IL)-6 gene expression of human fibroblast-like synoviocytes (FLSs) was assessed. p38 MAP kinase was constitutively expressed in human FLSs and activated in response to IL-1beta. A pyridinylimidazole compound, SB203580, inhibited p38 MAP kinase activity in vivo, since the activity of MAPKAP kinase-2 (a substrate of p38 MAP kinase) in IL-1beta-stimulated FLSs was totally suppressed by it. SB203580 concentration-dependently inhibited protein production and gene expression of IL-6 by human FLSs. The effect of SB203580 was dependent on de novo protein synthesis. SB203580 significantly reduced the stability of IL-6 mRNA without affecting the rate of IL-6 gene transcription. Here, we provide evidence that p38 MAP kinase is activated in response to IL-1beta in human FLSs and is involved in IL-6 synthesis by stabilizing IL-6 mRNA.
Miyazawa
K
K
Central Research Laboratories, Kissei Pharmaceutical Co., Ltd., Nagano-Pref. 399-8304, Japan. keijimiya@aol.com
Mori
A
A
Miyata
H
H
Akahane
M
M
Ajisawa
Y
Y
Okudaira
H
H
D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology / Q000473:pathology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology* / Q000502:physiology; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins; D007700:Kinetics; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B / Q000378:metabolism; D010003:Osteoarthritis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D013583:Synovial Membrane / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2
D000893:Anti-Inflammatory Agents; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D003513:Cycloheximide; D003609:Dactinomycin; D007093:Imidazoles; D007375:Interleukin-1; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D011725:Pyridines; D011994:Recombinant Proteins; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C093642:SB 203580