Differential roles of CB1 and CB2 cannabinoid receptors in mast cells
Differential roles of CB1 and CB2 cannabinoid receptors in mast cells
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DOI：
10.4049/jimmunol.170.10.4953
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发表时间：
2003-05-15
影响因子：
4.4
通讯作者：
Turner, H
中科院分区：
文献类型：
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作者：
Samson, MT;Small-Howard, A;Turner, H
大麻素对免疫反应的调节是大麻滥用的病理后果，也是该药物治疗应用的潜在结果。此外，内源性大麻素是生理免疫调节剂。在本报告中，我们描述了肥大细胞系 RBL2H3 暴露于大麻素后发生的基因转录变化。大麻素暴露会导致许多基因的转录水平发生显着变化，其作用既独立于 FcepsilonRI 的免疫受体刺激，又与 FcepsilonRI 的免疫受体刺激协同作用。在两个肥大细胞系中，我们观察到与 CB1 和 CB2 大麻素受体亚型相对应的 mRNA 和蛋白质表达，这与 CBI 仅限于 CNS 的普遍观点相反。我们表明，两种亚型的共表达在肥大细胞中并不存在功能冗余。对大麻素应用下游信号通路的分析表明，细胞外信号调节激酶 AKT 和选定的 AKT 靶标子集的激活是通过肥大细胞中的 CB2 配体和非选择性 CB1/CB2 激动剂完成的。 CB1 抑制不会影响大麻素对 AKT 或细胞外信号调节激酶的激活，表明 CB2 是该细胞环境中这些激酶的主要调节受体。然而，CB1 受体在这些肥大细胞中发挥作用，因为它们有助于抑制分泌反应。
Cannabinoid modulation of immune responses is a pathological consequence of marijuana abuse and a potential outcome of therapeutic application of the drug. Moreover, endogenous cannabinoids are physiological immune regulators. In the present report, we describe alterations in gene transcription that occur after cannabinoid exposure in a mast cell line, RBL2H3. Cannabinoid exposure causes marked changes in the transcript levels for numerous genes, acting both independently of and in concert with immunoreceptor stimulation via FcepsilonRI. In two mast cell lines, we observed mRNA and protein expression corresponding to both CB1 and CB2 cannabinoid receptor isoforms, contrary to the prevailing view that CBI is restricted to the CNS. We show that coexpression of the two isoforms is not functionally redundant in mast cells. Analysis of signaling pathways downstream of cannabinoid application reveals that activation of extracellular signal-regulated kinase, AKT, and a selected subset of AKT targets is accomplished by CB2 ligands and nonselective CB1/CB2 agonists in mast cells. CB1 inhibition does not affect AKT or extracellular signal-regulated kinase activation by cannabinoids, indicating that CB2 is the predominant regulatory receptor for these kinases in this cell context. CB1 receptors are, however, functional in these mast cells, since they can contribute to suppression of secretory responses.