Sido Jessica M, Nagarkatti Prakash S, Nagarkatti Mitzi
Department of Pathology, Microbiology, & Immunology, University of South Carolina School of Medicine, Columbia, SC, USA.
WJB Dorn Veterans Affairs Medical Center, Columbia, SC, USA.
Eur J Immunol. 2016 Jun;46(6):1472-9. doi: 10.1002/eji.201546181.
Endocannabinoids are endogenous ligands for the cannabinoid (CB) receptors which include anandamide (AEA) and 2-arachidonyl glycerol (2-AG). 2-AG has been linked to inflammation due to its elevated expression in animal models of autoimmunity and hypersensitivity. However, administration of exogenous 2-AG has been shown to suppress inflammation making its precise role unclear. In the current study, we investigated the role of 2-AG following immunization of C57BL/6 (BL6) mice with methylated BSA (mBSA) antigen, which triggers both delayed-type hypersensitivity (DTH) and antibody response. We found that while naïve T cells and B cells expressed low levels of 2-AG, expression significantly increased upon activation. Furthermore, mBSA-immunized mice exhibited higher 2-AG concentration than naïve mice. Exogenous 2-AG treatment (40 mg/kg) in mBSA-immunized mice led to reduced DTH response, and decreased Th1 and Th17-associated cytokines including IL-6, IL-2, TNF-α, and the IgG response. Addition of 2-AG to activated popliteal lymph node (PopLN) cell cultures also inhibited lymphocyte proliferation. Together, these data show for the first time that activated T and B cells produce 2-AG, which plays a negative regulatory role to decrease DTH via inhibition of T-cell activation and proliferation. Moreover, these findings suggest that exogenous 2-AG treatment can be used therapeutically in Th1- or Th17-driven disease.
内源性大麻素是大麻素（CB）受体的内源性配体，包括花生四烯乙醇胺（AEA）和2-花生四烯酸甘油酯（2-AG）。在自身免疫和超敏反应的动物模型中，2-AG因其表达升高而与炎症相关。然而，外源性给予2-AG已被证明可抑制炎症，这使得其确切作用尚不清楚。在本研究中，我们在用甲基化牛血清白蛋白（mBSA）抗原免疫C57BL/6（BL6）小鼠后，研究了2-AG的作用，mBSA抗原可引发迟发型超敏反应（DTH）和抗体反应。我们发现，虽然未活化的T细胞和B细胞表达低水平的2-AG，但活化后其表达显著增加。此外，mBSA免疫的小鼠比未免疫的小鼠表现出更高的2-AG浓度。在用mBSA免疫的小鼠中进行外源性2-AG处理（40mg/kg）导致DTH反应降低，并降低了包括IL-6、IL-2、TNF-α在内的Th1和Th17相关细胞因子以及IgG反应。向活化的腘窝淋巴结（PopLN）细胞培养物中添加2-AG也抑制淋巴细胞增殖。总之，这些数据首次表明活化的T细胞和B细胞产生2-AG，其通过抑制T细胞活化和增殖对降低DTH起负调节作用。此外，这些发现表明外源性2-AG处理可用于治疗Th1或Th17驱动的疾病。
