ETHANOL-INDUCED ALTERATIONS OF MONOKINE PRODUCTION

乙醇引起的单碱生产变化

• 批准号: 2045280
• 负责人: Gyongyi Szabo
• 金额: $ 7.77万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-02-01 至 1995-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2045280
• 关键词: biological signal transduction; calcium flux; chemical structure function; cyclic AMP; ethanol; gene expression; human tissue; immune system; interleukin 6; messenger RNA; monokines; prostaglandin E; transforming growth factors

Altered monocyte functions are major contributors to the development of alcohol induced immune and metabolic abnormalities. Ethanol-induced elevated M0 Prostaglandin E2 (PGE2) is the mediator of many alcohol related M0 and T lymphocyte defects. Decreased production of inflammatory monokines, such as TNFalpha, has been reported in rats after acute ethanol uptake. Our data on human M0 indicate that single in vitro ethanol treatment decreases the production of biologically active M0 TNFalpha and IL-6 with concomitant increase in the production of inhibitory M0 mediators, such as PGE2 and Transforming Growth Factorbeta (TGFbeta). High PGE2 levels downregulate Mo TNFalpha production via elevated cyclic AMP (cAMP). However our data indicate the existence of a PGE2-independent pathway for monokine regulation by ethanol. Ethanol has been shown to increase cAMP levels in lymphoid cells. Increases in M0 cAMP level has the potential to regulate bioactive TNFalpha production and gene expression. Therefore, our hypothesis is that ethanol can regulate the production of monokines, particularly that of TNFalpha, via a cAMP dependent pathway by directly increasing M0 cAMP levels. furthermore, the differential effect of chronic ethanol treatment on M0 TNFalpha production may be related to alcohol induced repetitive PGE2 elevations which can desensitize M0 to PGE2 mediated downregulation of TNFalpha production during chronic alcohol treatment. Consequently, we propose to study the involvement of cAMP in the mechanism by which acute and chronic ethanol treatment alters the production of MO TNFalpha, IL-6 and TGFbeta at the levels of mRNA and bioactivity. Changes in the intracellular cAMP following ethanol exposure as well as the effect of cAMP agonists and antagonists on the ethanol induced alterations of monokine production will be assessed. The role of PGE2 in ethanol induced monokine and cAMP alterations will also be investigated. In addition to affecting cAMP signal transduction, ethanol can also amplify signal transduction via Ca++ mobilization. Intracellular Ca++ levels were shown to rapidly increase in response to ethanol in rat M0. Ca++ increase results in M0 PGE2 production which has the potential for regulation of monokine production. Consequently, we hypothesize that ethanol related increases in intracellular Ca++ levels in M0 contribute to altered M0 responses after alcohol treatment. Therefore, we propose to study the ethanol induced changes in the level of intracellular Ca++ and correlate them with its effect on M0 PGE2 production. Alcohol induced intracellular Ca++ levels will be evaluated in the individual M0 on the Attofluor.

单核细胞功能改变是发展的主要因素。 酒精引起的免疫和代谢异常。乙醇诱导 升高的M0前列腺素E2(PGE2)是许多酒精的中介物 相关的M0和T淋巴细胞缺陷。减产 据报道，炎症性单因子，如肿瘤坏死因子α，在大鼠体内 急性酒精摄取症。我们在人类M0上的数据表明，单个人在体外 乙醇处理减少生物活性M0的产生 肿瘤坏死因子α和白介素6伴随着细胞产量的增加 抑制性M0介体，如PGE2和转化生长因子β (TGFbeta)。高PGE2水平通过下调Mo TNFpha的产生 环磷酸腺苷(CAMP)升高。然而，我们的数据表明， 乙醇调节单核细胞因子的PGE2非依赖性途径。乙醇 已被证明可以增加淋巴样细胞中的cAMP水平。增加了 M0 cAMP水平有可能调节生物活性肿瘤坏死因子α的产生 和基因表达。因此，我们的假设是乙醇可以 通过以下途径调节单核细胞的产生，特别是肿瘤坏死因子α 通过直接增加M0 cAMP水平实现cAMP依赖途径。 此外，慢性乙醇处理对M0的不同影响 肿瘤坏死因子α的产生可能与酒精诱导的重复PGE2有关 可使M0对PGE2脱敏的上调介导的下调 慢性酒精治疗期间肿瘤坏死因子α的产生。因此，我们 建议研究cAMP参与急性心肌梗死的机制 慢性乙醇治疗改变了MO、TNFpha、IL-6的产生 和TGFβ在mRNA和生物活性水平上的差异。的变化 乙醇暴露后细胞内cAMP的变化及其对细胞内cAMP的影响 CAMP激动剂和拮抗剂对乙醇引起的细胞毒性改变的影响 将对单核细胞的生产进行评估。前列腺素E_2在乙醇中的作用 诱导的单核细胞和cAMP改变也将被调查。在……里面 除了影响cAMP信号转导，乙醇还可以放大 钙离子动员的信号转导。细胞内钙离子水平 在大鼠M0对乙醇的反应迅速增强。CA++ 增加M0 PGE2产量，这有可能 对单核细胞生产的监管。因此，我们假设 酒精引起的M0细胞内钙离子水平升高与酒精有关 改变酒精治疗后的M0反应。因此，我们建议 乙醇诱导的细胞内钙离子水平变化的研究 并将它们与其对M0-PGE2产生的影响相关联。酒精 诱导的细胞内钙水平将在个体M0中进行评估 在阿托弗洛号上。