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首页> 外文期刊>Journal of Neuroimmunology: Official Bulletin of the Research Committee on Neuroimmunology of the World Federation of Neurology >Inverse agonism of cannabinoid CB1 receptor blocks the adhesion of encephalitogenic T cells in inflamed brain venules by a protein kinase A-dependent mechanism.
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Inverse agonism of cannabinoid CB1 receptor blocks the adhesion of encephalitogenic T cells in inflamed brain venules by a protein kinase A-dependent mechanism.

机译：大麻素CB1受体的反向激动作用可通过蛋白激酶A依赖性机制阻断发炎性脑小静脉中脑致病性T细胞的粘附。

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It is well known that the cannabinoid system has a significant role in the regulation of the immune responses. Cannabinoid receptors CB1 and CB2 are expressed on T lymphocytes and mediate the immunomodulatory effects of cannabinoids on T cell functions. Here we show that the treatment of proteolipid protein (PLP)139-151-specific T cells with SR141716A, a CB1 inverse agonist and prototype of the diarylpyrazoles series, induced a strong inhibition of firm adhesion in inflamed brain venules in intravital microscopy experiments. In contrast, SR144528, a potent CB2 inverse agonist, had no significant effect on both rolling and arrest of activated T cells. In addition, two analogs of SR141716A and CB1 inverse agonists, AM251 and AM281 inhibited encephalitogenic T cell adhesion suggesting that selective CB1 inverse agonism interfere with lymphocyte trafficking in the CNS. Flow cytometry experiments showed that CB1 inverse agonists have no effect on adhesion molecule expression suggesting that CB1 blockade interferes with signal transduction pathways controlling T cell adhesion in inflamed brain venules. In addition, integrin clustering was not altered after treatment with CB1 inverse agonists suggesting that adhesion blockade is not due to the modulation of integrin valency. Notably, the inhibitory effect exerted by AM251 and AM281 on the adhesive interactions was completely reverted in the presence of protein kinase A (PKA) inhibitor H89, suggesting that cAMP and PKA activation play a key role in the adhesion blockade mediated by CB1 inverse agonists. To further strengthen these results and unveil a previously unknown inhibitory role of cAMP on activated T cell adhesion in vivo in the context of CNS inflammation, we showed that intracellular increase of cAMP induced by treatment with Bt2cAMP, a permeable analog of cAMP, and phosphodiesterase (PDE) inhibitor theophylline efficiently blocked the arrest of encephalitogenic T cells in inflamed brain venules. Our data show that modulation of CB1 function has anti-inflammatory effects and suggests that inverse agonism of CB1 block signal transduction mechanisms controlling encephalitogenic T cells adhesion in inflamed brain venules by a PKA-dependent mechanism.
机译：众所周知，大麻素系统在免疫应答的调节中起着重要作用。大麻素受体CB1和CB2在T淋巴细胞上表达，并介导大麻素对T细胞功能的免疫调节作用。在这里，我们显示，在活体显微镜实验中，用SR141716A，CB1反向激动剂和二芳基吡唑系列的原型对蛋白脂蛋白（PLP）139-151特异性T细胞进行治疗，可以强烈抑制发炎的脑静脉中的牢固粘附。相反，有效的CB2反向激动剂SR144528对活化T细胞的滚动和停滞均无显着影响。另外，SR141716A和CB1反向激动剂的两个类似物AM251和AM281抑制了致脑性T细胞粘附，表明选择性CB1反向激动作用干扰了CNS中的淋巴细胞运输。流式细胞仪实验表明，CB1反向激动剂对黏附分子的表达没有影响，表明CB1阻滞干扰发炎的脑小静脉中T细胞黏附的信号转导途径。此外，在用CB1反向激动剂治疗后，整合素簇没有改变，这表明粘附阻滞不是由于整合素价的调节引起的。值得注意的是，在蛋白激酶A（PKA）抑制剂H89的存在下，AM251和AM281对黏附相互作用的抑制作用已完全恢复，这表明cAMP和PKA活化在CB1反向激动剂介导的黏附阻滞中起关键作用。为了进一步加强这些结果并揭示cAMP对中枢神经系统炎症在体内激活的T细胞粘附的抑制作用，我们证明了用Bt2cAMP，cAMP的可渗透性类似物和磷酸二酯酶处理可诱导cAMP的细胞内增加（ PDE）抑制剂茶碱有效阻断了发炎的脑小静脉中促脑性T细胞的阻滞。我们的数据表明，CB1功能的调节具有抗炎作用，并表明CB1激动剂的反向激动作用是通过PKA依赖性机制控制发炎的脑静脉中脑源性T细胞粘附的信号传导机制。

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