Studies on the COX inhibitor-induced PAF production and its pharmacological significance

COX抑制剂诱导PAF产生及其药理意义的研究

• 批准号: 09672210
• 负责人: OHUCHI Kazuo
• 金额: $ 2.24万
• 依托单位: Tohoku University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09672210/
• 关键词: platelet-activating factor; tumor necrosis factor-alpha; thapsigargin; indomethacin; macrophage; prostaglandin E2; SK & F 98625; E6123; L-652,731; prostaglandin E_2; SK&F98625

Stimulation of rat peritoneal macrophages by thapsigargin (46.1 nM) increased levels of tumor necrosis factor-a and prostaglandin E2 in the conditioned medium.Platelet-activating factor was not detected in the conditioned medium, but the level of cell-associated platelet-activating factor was increased transiently by thapsigargin.The receptor antagonists of platelet-activating factor such as E6123, L-652,731and CV-6209 inhibited thapsigargin-induced production of tumor necrosis factor-alpha. The cyclooxygenase inhibitor indomethacin inhibited prostaglandin E2production, and further enhanced thapsigargin-induced tumor necrosis factor-alphaproduction in parallel with further increase in cell-associated platelet-activating factor production.The enhancement of tumor necrosis factor-a production induced by thapsigarginplus indomethacin was also inhibited by E6123, L-652,731 and CV-6209.However, exogenously added platelet-activating factor up to 100 nM did not stimulate production of tumor necrosis factor-a.The level of tumor necrosis factor-alpha mRNA was increased by thapsigargin, but was lowered by the platelet-activating factor antagonist E6123, suggesting that the inhibition of tumor necrosis factor-a production by the platelet-activating factor antagonist is induced at the level of mRNA for tumor necrosis factor-a.These findings suggested that concurrently produced cell-associated platelet-activating factor up-regulates production of tumor necrosis factor-a by acting as an intracellular signaling molecule, and the antagonists of platelet-activating factor might penetrate into the cells and antagonize the action of intracellular platelet-activating factor.

毒胡萝卜素对大鼠腹腔巨噬细胞的刺激作用（46.1 nM）增加了条件培养基中肿瘤坏死因子-α和前列腺素E2的水平。在条件培养基中未检测到血小板活化因子，但细胞相关的血小板活化因子的水平被毒胡萝卜素瞬时增加。血小板活化因子的受体拮抗剂如E6123，L-652，731和CV-6209抑制毒胡萝卜素诱导的肿瘤坏死因子-α的产生。环氧合酶抑制剂吲哚美辛抑制前列腺素E2的产生，并进一步增强thapsiglide诱导的肿瘤坏死因子-α的产生，同时进一步增加细胞相关血小板活化因子的产生。高达100 nM的外源性加入的血小板活化因子不刺激肿瘤坏死因子-α的产生。毒胡萝卜素增加了肿瘤坏死因子-α mRNA的水平，但血小板活化因子拮抗剂E6123降低了肿瘤坏死因子-α mRNA的水平，这表明血小板活化因子拮抗剂对肿瘤坏死因子-a产生的抑制是在肿瘤坏死因子-a的mRNA水平上诱导的。通过作为细胞内信号分子调节肿瘤坏死因子-α的产生，并且血小板活化因子的拮抗剂可以渗透到细胞内并拮抗细胞内血小板活化因子的作用。

项目成果

Yamada,M., et al.: "Prostaglandin E_2 production dependent upon cyclooxygenase-1 and cyclooxygenase-2 and its contradictory modulation by auranofin in rat peritoneal macrophages" J.Pharmacol.Exp.Ther.281. 1005-1012 (1997)

Yamada,M., et al.：“前列腺素 E_2 的产生依赖于环加氧酶-1 和环加氧酶-2 及其在大鼠腹膜巨噬细胞中金诺芬的矛盾调节”J.Pharmacol.Exp.Ther.281。

Masateru Yamada, Gaku Ichinowatari, Atsuo Tanimoto, Hiroshi Yaginuma, Suetsugu Mue, Kazuo Ohuchi: "Possible participation of intracellular PAF in TNF-alpha production in stimulated macrophages" Inflammation Res.46 Supplement 3. S236 (1997)

Masateru Yamada、Gaku Ichinowatari、Atsuo Tanimoto、Hiroshi Yaginuma、Suetsugu Mue、Kazuo Ohuchi：“细胞内 PAF 可能参与受刺激巨噬细胞中 TNF-α 的产生” Inflammation Res.46 Supplement 3. S236 (1997)

Ohuchi,K.,et al.: "Possible participation of platelet-activating factor in tumor promoter-induced TNF-α production" Cancer Detect.Prev.22. S-225 (1998)

Ohuchi, K. 等人：“血小板激活因子可能参与肿瘤启动子诱导的 TNF-α 产生”Cancer Detect.Prev.22 (1998)。