| Project/Area Number |
09672211
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Biological pharmacy
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| Research Institution | Tohoku University |
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Principal Investigator |
HIRASAWA Noriyasu Tohoku University, Faculty of Pharmaceutical Sciences, Associate Professor, 薬学部, 助教授 (80181155)
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| Co-Investigator(Kenkyū-buntansha) |
OHUCHI Kazuo Tohoku University, Faculty of Pharmaceutical Sciences, Professor, 薬学部, 教授 (20006357)
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| Project Period (FY) |
1997 – 1998
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| Project Status |
Completed (Fiscal Year 1998)
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| Budget Amount *help |
¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 1998: ¥700,000 (Direct Cost: ¥700,000)
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| Keywords | mast cells / steroidal anti-inflammatory drug / MAP kinase / interleukin 4 / phosphatidylinositol 3-kinase / Raf-1 / p38 MAP kinase / c-Jun N-terminal kinase / wortmannin |
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| Research Abstract |
We examined whether steroidal anti-inflammatory drugs inhibit cytokine production through inhibition of MAP kinase activation.
1. Effects of the steroidal anti-inflammatory drug dexamethasone on MAP kinase activation
. Pretreatment of rat mast cell line RBL-2H3 cells with dexamethasone (10 and 100 nM) for 18 hinhibited the antigen-induced increase in c-Jun N-terminal kinase (JNK) activity. The phosphory-lation of c-Jun induced by the antigen stimulation was also reduced by pretreatment with dexamethasone. These findings indicate that dexamethasone inhibits the antigen-induced activation of JNK resulting in the inhibition of the activation of the transcription factor AP-1.
2. Effects of the inhibitors of MA P kinase activation on the antigen-induced IL-4production.
Wortmannin and LY294002, the P13-kinase inhibitors, inhibited the antigen-induced p38 MAP kinase and JNK.Wortmannin and p38 MAP kinase inhibitors inhibited both the antigen-induced increase in the IL-4 mRNA level and IL-4 production. In addition, retinoids, which can inhibit AP-1activity, also inhibit IL-4 production. Thus it is demonstrated that the inhibition of MAP kinase activation or the inhibition of AP-1 activity resulted in the inhibition of IL-4 production.
3. The mechanisms by which dexamethasone inhibits the antigen-induced MAPkinase activation. Dexamethasone inhibited the phosphorylation of MAPKKK Raf-1 without affecting Raf-1translocation to membrane fraction.
Conclusion
These results suggested that one of the mechanisms by which steroidal anti-inflammatory drugs inhibits IL-4 production is the inhibition of MAP kinase activation. Thus, the drugs which inhibit MAP kinase activation might be a novel anti-inflammatory drugs.
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