Studies on cytokine-induced sleep in prostanoid-related gene-manipulated mice

前列腺素相关基因操作小鼠细胞因子诱导睡眠的研究

• 批准号: 14580755
• 负责人: HAYAISHI Osamu
• 金额: $ 2.62万
• 依托单位: Osaka Bioscience Institute
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14580755/
• 关键词: inflammation; sytokine; IL-1β; TNF-α; Sleep; Prostaglandin; knockout mouse

Infectious illness is associated with an increase in the amount of sleep and causes the production of proinflammatory cytokines and induction of cyclooxygenase-2 (COX-2), which is the key enzyme of the biosynthesis of prostaglandins (PGs). Both IL-1β and PGD_2 promote sleep in rats and mice. Pretreatment of COX-2 inhibitor reportedly blocked the IL-1β-promoted sleep in rats. Therefore, PGs are considered to mediate the somnogenic effect of IL-1β in rats. However, little is known about the molecular interaction between PGs and cytokines in the sleep-wake regulation in mice. Here, we employed the PGD_2 receptor-knockout mice and highly selective COX-2 inhibitor NS-398 to examine the involvement of PGD2 in the somnogenic effect of IL-1β in mice. IL-1β increased total amount of non-rapid eye movement (NREM) sleep in both wild-type (WT) and PGD_2 receptor-knockout mice and concomitantly reduced body temperature and locomotor activity for 6h after the intraperitoneal injection at 8 p.m. Pretreatment ofNS-398 inhibited neither spontaneous nor IL-1β-induced sleep in WT mice. These results indicate that PGD_2 is not involved in the somnogenic effect of IL-1β in mice.

感染性疾病与睡眠时间增加有关，并导致促炎细胞因子的产生和环氧合酶-2(COX-2)的诱导，COX-2是前列腺素(PGs)生物合成的关键酶。IL-1β和PgD_2对大鼠和小鼠的睡眠均有促进作用。据报道，COX-2抑制剂的预处理阻断了IL-1β促进的大鼠睡眠。因此，PGs被认为介导了IL-1β对大鼠的催眠作用。然而，关于PGs和细胞因子在小鼠睡眠-觉醒调节中的分子相互作用知之甚少。在这里，我们利用PGD2受体敲除小鼠和高选择性COX-2抑制剂NS-398来研究PGD2在IL-1β对小鼠的催眠作用中的作用。IL-1β增加了野生型(WT)和PgD2受体基因敲除小鼠的非快速眼动睡眠总量，并在晚上8点腹腔注射后6小时内降低了体温和运动能力。NS398对WT小鼠的自发睡眠和IL-1β诱导的睡眠均无抑制作用。提示PgD_2不参与IL-1β对小鼠的催眠作用。

项目成果

Taniike, M., Mohri, I., Eguchi, N., Beuckmann, C.T., Suzuki, K., Urade, Y.: "Perineuronal oligodendrocytes protect against neuronal apoptosis through the production of lipocalin-type prostaglandin D synthase in a genetic demyelinating model."J.Neurosci..

Taniike, M.、Mohri, I.、Eguchi, N.、Beuckmann, C.T.、Suzuki, K.、Urade, Y.：“神经元周围少突胶质细胞通过在遗传脱髓鞘中产生脂运载蛋白型前列腺素 D 合酶来防止神经元凋亡

Irikura, D.: "Cloning, Expression, Crystallization, and Preliminary X-Ray Analysis of Recombinant Mouse Lipocalin-type Prostaglandin D Synthase, a Somnogen-Producmg Enzyme"J. Biochem.. 133. 29-32 (2003)

Irikura, D.：“重组小鼠脂质运载蛋白型前列腺素 D 合酶（一种催眠酶）的克隆、表达、结晶和初步 X 射线分析”J。

Kubata, B.K., Duszenko M., Kabututu, Z., Rawer, M., Szallies, A., Inui, T., Urade, Y., Hayaishi, O.: "Enzymatic formation of prostaglandin D_2, E_2, and F_2 in the parasitic protozoan Trypanosoma brucei."Elsevier.

Kubata, B.K., Duszenko M., Kabututu, Z., Rawer, M., Szallies, A., Inui, T., Urade, Y., Hayaishi, O.：“前列腺素 D_2、E_2 和 F_2 的酶促形成

Eguchi, N., et al.: "Sleep in transgenic and gene-knockout mice for lipocalin-type prostaglandin D synthase."Oxygen and Life -0xygenases, Oxidases and Lipid Mediators-.(Eds.by Ishimura, Y., Nozaki, M., Yamamoto, S., Shimizu, T., Narumiya, S., and Mitani,

Eguchi, N., 等人：“转基因和基因敲除小鼠中脂质运载蛋白型前列腺素 D 合酶的睡眠。”氧与生命 -0 加氧酶、氧化酶和脂质介质 -。（Ishimura, Y.、Nozaki 编辑，

Lazarus, M., Kubata, B.K., Eguchi, N., Fujitani Y., Urade, Y., Hayaishi, O.: "Biochemical characterization of mouse microsomal prostaglandin E synthase-1 and its colocalization with cyclooxygenase-2 in peritoneal macrophages."Arch.Biochem.Biophys.. 397(2)

Lazarus, M., Kubata, B.K., Eguchi, N., Fujitani Y., Urade, Y., Hayaishi, O.：“小鼠微粒体前列腺素 E 合酶 1 的生化特征及其与腹膜巨噬细胞中环加氧酶 2 的共定位。