N-Methyl-D-Aspartate and σ-Ligands Change the Production of Interleukins 8 and 10 in Lymphocytes through Modulation of the NMDA Glutamate Receptor
N-Methyl-D-Aspartate and σ-Ligands Change the Production of Interleukins 8 and 10 in Lymphocytes through Modulation of the NMDA Glutamate Receptor
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DOI：
10.1159/000204234
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发表时间：
2009-01-01
影响因子：
2.4
通讯作者：
Mikeladze, David G.
中科院分区：
文献类型：
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作者：
Kvaratskhelia, Eka;Maisuradze, Ekaterine;Mikeladze, David G.
人类T淋巴细胞同时表达离子型和代谢型谷氨酸受体，控制免疫反应、细胞激活、成熟和死亡。本研究观察了N-甲基-D-天冬氨酸(NMDA)和Sigma-1受体配体对人白血病Jurkat细胞和外周血淋巴细胞分泌促炎细胞因子IL-8和抗炎细胞因子IL-10的影响。我们发现NMDA增加了IL-8，减少了IL-10的分泌，并且Sigma配体调节了NMDA的作用。此外，NMDA和Sigma配体的作用与一氧化氮(NO)含量相关，提示细胞内NO浓度可能在细胞因子的合成中起主要作用。对NMDA谷氨酸受体NR2A和NR2B亚基的Western blotting显示，长期(48h)谷氨酸作用于正常血浆水平(1×10(-5)M)的PBL，而不是低浓度(0.3×10(-6)M)的谷氨酸，可能通过内化下调NR2A亚基的表达。此外，我们还发现，未内化NR2A的PBL分泌的IL-10比下调NR2A的PBL少；在此条件下，NF-kappa B的转录活性增加，而c-Fos的转录活性降低。这些发现表明，核因子-kappa B和c-Fos的活性控制着IL8和IL10基因的表达，这取决于NMDA受体的亚基组成。综上所述，我们认为淋巴细胞仅在低谷氨酸环境中表达活跃的NMDA受体。版权所有(C)2009 S.Karger AG，巴塞尔
Human T lymphocytes express both ionotropic and metabotropic glutamate receptors that control immune responses, cell activation, maturation and death. In this study, we examined the effect of N-methyl-D-aspartate (NMDA) and sigma 1-receptor ligands on the secretion of the proinflammatory chemokine interleukin 8 (IL-8) and the anti-inflammatory cytokine interleukin 10 (IL-10) in human leukemia Jurkat cells and peripheral blood lymphocytes (PBLs). We have shown that NMDA increased IL-8 and decreased IL-10 secretion and that sigma-ligands modulated the action of NMDA. Moreover, the effects of NMDA and sigma-ligands were interrelated with the nitric oxide (NO) content, suggesting that the intracellular concentration of NO could play a major role in the synthesis of cytokines. Western blots against the NR2A and NR2B subunits of the NMDA glutamate receptor revealed that long-term (48 h) treatment of PBLs with glutamate at concentrations within normal plasma levels (1 X 10(-5) M), in contrast to low concentrations (0.3 X 10(-6) M), downregulates the NR2A subunit, probably by internalization. Furthermore, we found that PBLs with noninternalized NR2A secreted less IL-10 than lymphocytes with downregulated NR2A; under these conditions, the transcriptional activity of NF-kappa B was increased whereas the transcriptional activity of c-Fos was decreased. These findings implicate that the activities of NF-kappa B and c-Fos control the expression of the IL8 and IL10 genes, depending on the subunit composition of the NMDA receptor. In conclusion, we suggest that lymphocytes express an active NMDA receptor only in a low-glutamate milieu. Copyright (C) 2009 S. Karger AG, Basel