Inosine inhibits inflammatory cytokine production by a posttranscriptional mechanism and protects against endotoxin-induced shock
Inosine inhibits inflammatory cytokine production by a posttranscriptional mechanism and protects against endotoxin-induced shock
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DOI：
10.4049/jimmunol.164.2.1013
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发表时间：
2000-01-15
影响因子：
4.4
通讯作者：
Szabó, C
中科院分区：
文献类型：
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作者：
Haskó, G;Kuhel, DG;Szabó, C
细胞外嘌呤，包括腺苷和ATP，是一种有效的内源性免疫调节分子，肌苷是这些嘌呤的降解产物，在细胞代谢应激（如炎症或缺血）的条件下，肌苷可以在细胞外空间达到高浓度。在本研究中，我们研究了细胞外肌苷是否可以影响炎症/免疫过程。在免疫刺激的巨噬细胞和脾细胞中，肌苷能有效抑制促炎细胞因子tnf - α、IL-1、IL-12、巨噬炎性蛋白-1 α和ifn - γ的产生，但不能改变抗炎细胞因子IL-10的产生。肌苷的作用不需要核苷转运体的细胞摄取，并且通过阻断腺苷A和A受体部分逆转，肌苷通过转录后机制抑制细胞因子的产生。在小鼠内毒素模型中，肌苷的活性不依赖于p38和p42/p44丝裂原活化蛋白激酶的激活、c-Jun末端激酶的磷酸化、抑制因子kappa B的降解和细胞内cAMP的升高，肌苷抑制了促炎细胞因子的产生和死亡率。综上所述，肌苷具有多种抗炎作用。这些发现，再加上肌苷具有非常低的毒性，表明这种药物可能用于治疗炎症性/缺血性疾病。
Extracellular purines, including adenosine and ATP, are potent endogenous immunomodulatory molecules, Inosine, a degradation product of these purines, can reach high concentrations in the extracellular space under conditions associated with cellular metabolic stress such as inflammation or ischemia, In the present study, we investigated whether extracellular inosine can affect inflammatory/immune processes. In immunostimulated macrophages and spleen cells, inosine potently inhibited the production of the proinflammatory cytokines TNF-alpha, IL-1, IL-12, macrophage-inflammatory protein-1 alpha, and IFN-gamma, but failed to alter the production of the anti-inflammatory cytokine IL-10. The effect of inosine did not require cellular uptake by nucleoside transporters and was partially reversed by blockade of adenosine A, and A, receptors, Inosine inhibited cytokine production by a posttranscriptional mechanism. The activity of inosine was independent of activation of the p38 and p42/p44 mitogen-activated protein kinases, the phosphorylation of the c-Jun terminal kinase, the degradation of inhibitory factor kappa B, and elevation of intracellular cAMP, Inosine suppressed proinflammatory cytokine production and mortality in a mouse endotoxemic model. Taken together, inosine has multiple anti-inflammatory effects. These findings, coupled with the fact that inosine has very low toxicity, suggest that this agent may be useful in the treatment of inflammatory/ischemic diseases.