Cross-talk between Gs- and Gq-coupled pathways in regulation of interleukin-4 by A2B adenosine receptors in human mast cells
Cross-talk between Gs- and Gq-coupled pathways in regulation of interleukin-4 by A2B adenosine receptors in human mast cells
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DOI：
10.1124/mol.106.022780
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发表时间：
2006-08-01
影响因子：
3.6
通讯作者：
Feoktistov, Igor
中科院分区：
文献类型：
--
作者：
Ryzhov, Sergey;Goldstein, Anna E.;Feoktistov, Igor
人肥大细胞表达功能性A（2A）和A（2B）腺苷受体。然而，只有A（2B）而不是A（2A）的刺激导致白细胞介素（IL）-4的分泌，这是腺苷受体介导的B细胞IgE合成诱导中的重要步骤。在这项研究中，我们研究了HMC-1肥大细胞中A（2B）受体刺激与IL-4上调之间的细胞内途径。A（2A）和A（2B）受体都与G（s）蛋白偶联并刺激腺苷酸环化酶，但只有A（2B）通过与G（q）蛋白偶联刺激磷脂酶C β，导致蛋白激酶C活化和钙动员。抑制磷脂酶C β完全阻断A（2B）受体依赖性IL-4分泌。蛋白激酶C抑制剂2-{8-[（二甲氨基）甲基]-6，7，8，9-四氢吡啶并[1，2-a]吲哚-3-基}-3-（1-甲基-1H-吲哚-3-基）马来酰亚胺（Ro-32-0432）对A（2B）受体介导的IL-4分泌无影响，但抑制佛波醇12-肉豆蔻酸酯13-乙酸酯刺激的IL-4分泌。与此相反，螯合细胞内Ca 2+抑制A（2B）受体和离子霉素依赖性IL-4分泌。这种Ca ~（2+）敏感途径可能包括钙调神经磷酸酶和活化T细胞的核因子，因为A（2B）受体依赖性IL-4分泌被环孢菌素A或11 R-VIVIT肽阻断。G（s）-连接途径也在A（2B）受体依赖性刺激IL-4分泌中起作用;腺苷酸环化酶或蛋白激酶A的抑制减弱A（2B）受体依赖性IL-4分泌。虽然用毛喉素刺激腺苷酸环化酶本身不会增加IL-4的分泌，但它增强了2倍多杀性巴氏杆菌毒素和3倍离子霉素的作用。毛喉素和A（2B）受体的刺激上调NFATc 1蛋白水平。我们的结论是，A（2B）受体上调IL-4通过G（q）信号，这是加强通过与G（s）耦合途径的串扰。
Human mast cells express functional A(2A) and A(2B) adenosine receptors. However, only stimulation of A(2B), not A(2A), leads to secretion of interleukin (IL)-4, an important step in adenosine receptor-mediated induction of IgE synthesis by B-cells. In this study, we investigate intracellular pathways that link stimulation of A(2B) receptors to IL-4 up-regulation in HMC-1 mast cells. Both A(2A) and A(2B) receptors couple to G(s) proteins and stimulate adenylate cyclase, but only A(2B) stimulates phospholipase C beta through coupling to G(q) proteins leading to activation of protein kinase C and calcium mobilization. Inhibition of phospholipase C beta completely blocked A(2B) receptor-dependent IL-4 secretion. The protein kinase C inhibitor 2-{8-[(dimethylamino)methyl]-6,7,8,9-tetrahydropyrido[ 1,2-a] indol-3-yl}-3-(1-methyl-1H-indol-3-yl) maleimide (Ro-32-0432) had no effect on A(2B) receptor-mediated IL-4 secretion but inhibited phorbol 12-myristate 13-acetate-stimulated IL-4 secretion. In contrast, chelation of intracellular Ca2+ inhibited both A(2B) receptor- and ionomycin-dependent IL-4 secretion. This Ca2+-sensitive pathway probably includes calcineurin and nuclear factor of activated T cells, because A(2B) receptor-dependent IL-4 secretion was blocked with cyclosporin A or 11R-VIVIT peptide. G(s)-linked pathways also play a role in the A(2B) receptor- dependent stimulation of IL-4 secretion; inhibition of adenylate cyclase or protein kinase A attenuated A(2B) receptor-dependent IL-4 secretion. Although stimulation of adenylate cyclase with forskolin did not increase IL-4 secretion on its own, it potentiated the effect of Pasteurella multocida toxin by 2-fold and ionomycin by 3-fold. Both forskolin and stimulation of A(2B) receptors upregulated NFATc1 protein levels. We conclude that A(2B) receptors up-regulate IL-4 through G(q) signaling that is potentiated via cross-talk with G(s)-coupled pathways.