| Co-Investigator(Kenkyū-buntansha) |
IZUHARA Kenji Kyushu University, Faculty of Medicine, assistant professor, 医学部, 助手 (00270463)
TANAKA Yosuke Kyushu University, 医学部, 医員
YAMAOKA Kunihiro Kyushu University, 医学部, 医員
NIIRO Hiroaki Kyushu University, 医学部, 特別研究員
NAKASHIMA Hitoshi Kyushu University, Faculty of Medicine, assistant professor, 医学部, 助手 (70188960)
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| Research Abstract |
1) We investigated the effects of IL-4 and IL-1 on prostanoid synthesis in human neutrophils. Both cytokines inhibited their LPS-induced-PGE2 production, and their suppression was achieved by inhibiting cyclooxygense-2 mRNA expression. (Ref. 1)
2) We previously reported that IL-4 and IL-l0 suppressed prostanoid synthesis in human monocytes.
We questioned whether mitogen-activated protein kinase (MAPK) activation is involved in COX-2 expression in LPS-stimulated human monocytes. LPS induced the expression of COX-2 protein and COX-2 mRNA as well as the phospholylation and activation of extracellular signal-regulated protein kinase (ERK)2 and p38 MAPK in monocytes. The induction of COX-2 mRNA, COX-2 protein, and prostaglandin (PG) E2 by LPS was inhibited by the specific inhibitors of ERK2 and p38 MAPK.LPS-induced phosphorylation and activation of ERK2 was significantly inhibited by IL-4 and IL-10, while that of p38 MAPK was inhibited by IL-10, but not IL-4. These results suggested that the
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mechanisms of inhibition by IL-l0 and IL-4 of the LPS-induced expression of proinflammatory molecules could be ascribed to the regulatory effects of both cytokines on MAPK activation. (Ref. 2)
3) We also studied whether some known STAT molecule is stimulated by LPS, based on the finding that a GAS motif sequence is conserved in the promoter regions of human, mouse, and rat COX-2 genes.
Consequently, LPS induced activation of STAT5 in human monocytes, and this STATS activation occured in an indirect way via granulocyte-macrophage colony stimulating factor secreted by LPS- stimulated monocytes.Expression of COX-2 protein was partially reduced by treatment of anti-human GM-CSF Ab, Activation of STAT5 wa inhibited by either IL-10 or dexamethazone, but not by aspirin.IL-10 blocked activation of STATS indirectly by suppressing GM-CSF production, while Dex inhibited this activation both directly and indirectly.These results suggested that STAT5 plays an important role in activation of monocytes by LPS, and that STAT5 is another target for IL-10 and Dex to inhibit COX-2 expression. (Ref. 3)
4) In rheumatoid arthritis patients, polymorphonuclear leukocytes are an important cellular source of prostanoids. To determine whether PMNs from RA patients exhibit different profiles in prostanoid synthesis compared to those from healthy donors, we studied 20 RA patients. Without stimulation, PGE2 production by PMNs was much higher in the RA patients than in the healthy controls. COX-2 protein was thought to be responsible for this increased PGE2 production. Neither IL-4 nor IL-10 affected the production. In conclusion, our results raise the possibility that PMNs from RA patients contribute, at least in part, to the pathogenesis of RA by producing COX-2-derived prostanoids in vivo. (Ref. 4)
5) Since IL-10 was thought involved in pathogenesis of human diseases, we examined polymorphisms within human. IL-10 receptor cDNA gene sequenceby RT-PCR-RFLP.(Ref. 5) We further plan to examine the sensitivity of these polymorphisms for various immune disease. Less
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