Regulation of calcium by delta9-tetrahydrocannabinol

δ9-四氢大麻酚对钙的调节

• 批准号: 6850835
• 负责人: GAUTHAM K RAO
• 金额: $ 2.83万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-16 至 2006-08-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6850835
• 关键词: T lymphocyte; autoradiography; calcium; calcium flux; calmodulin dependent protein kinase; cannabinoids; enzyme linked immunosorbent assay; gel mobility shift assay; interleukin 2; laboratory mouse; lymphocyte proliferation; predoctoral investigator; protein kinase C; receptor expression

DESCRIPTION (provided by applicant): Previous studies from this and other laboratories have demonstrated that delta9-tetrahydrocannabinol (delta9-THC), the primary psychoactive constituent in marijuana, can inhibit the expression of interleukin (IL)-2 by activated T cells. However, it remains unclear what role the cannabinoid receptors play in the regulation of IL-2 production by cannabinoids. Here, experiments were performed in murine splenic T cells or human T cell lines, HPB-ALL and Jurkat E6-1. The splenic T cells express both CB1 and CB2 receptor transcripts whereas the human T cells only express CB2 transcripts. Moreover, while HPB-ALL cells express normal CB2 receptors, the Jurkat E6-1 cells express dysfunctional CB2 receptors. Preliminary data using these cell models suggest that delta9-THC may inhibit IL-2 production via a premature rise in intracellular calcium ([Ca2+]i) in a cannabinoid receptor dependent manner. This research will be further pursued with the hypothesis that the inhibition of interleukin-2 expression by delta9-THC involves cannabinoid receptor-dependent elevation of [Ca((]i activation of calcium-dependent enzymes, protein kinase C (PKC) and calcium-dependent calmodulin kinase II (CaMKII), and modulation of nuclear factor of activated T cells (NFAT) activation. Future studies will be performed in the splenic T cells or HPB-ALL cells with three specific aims (SA). SA1) Investigation of the mechanism of [Ca2+]i elevation by ((-THC. SA2) Characterization of the effect of delta9-THC on PKC and CaMKII activation. SA3) Examination of the effect of delta9-THC-mediated elevation in [Ca2+]i on NFAT activation and IL-2 expression.

描述(由申请人提供)： 该实验室和其他实验室以前的研究表明，大麻中的主要精神活性成分Delta9-四氢大麻酚(Delta9-THC)可以抑制激活的T细胞表达白细胞介素2(IL-2)。然而，目前还不清楚大麻素受体在大麻素对IL-2产生的调节中发挥了什么作用。在这里，实验是在小鼠脾T细胞或人T细胞系HPB-ALL和Jurkat E6-1上进行的。脾T细胞表达CB1和CB2受体转录本，而人T细胞仅表达CB2转录本。此外，HPB-ALL细胞表达正常的CB2受体，Jurkat E6-1细胞表达功能失调的CB2受体。使用这些细胞模型的初步数据表明，Delta9-THC可能通过依赖大麻素受体的方式过早地增加细胞内钙([Ca+]i)来抑制IL-2的产生。本研究将进一步假设Delta9-THC抑制IL-2的表达涉及依赖大麻素受体的[Ca(()]i)上调钙依赖的酶、蛋白激酶C(PKC)和钙依赖的钙调蛋白激酶II(CaMKII)的激活，以及调节活化的T细胞(NFAT)的激活。未来的研究将在有三个特定目的(SA)的脾T细胞或HPB-ALL细胞中进行。SA1)探讨((-THC)升高[Ca2+]i的机制。SA2)Delta9-THC对PKC和CaMKII激活的影响的特征。SA3)检测Delta9-THC介导的[Ca~(2+)]i升高对NFAT激活和IL-2表达的影响。