UP-REGULATION OF MONOCYTIC IL-10 BY TUMOR-NECROSIS-FACTOR-ALPHA AND CAMP ELEVATING DRUGS
UP-REGULATION OF MONOCYTIC IL-10 BY TUMOR-NECROSIS-FACTOR-ALPHA AND CAMP ELEVATING DRUGS
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DOI：
10.1093/intimm/7.4.517
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发表时间：
1995-04-01
影响因子：
4.4
通讯作者：
VOLK, HD
中科院分区：
文献类型：
--
作者：
PLATZER, C;MEISEL, C;VOLK, HD
众所周知，内毒素[脂多糖（LPS）]诱导单核细胞产生促炎细胞因子，随后分泌抗炎细胞因子IL-10。IL-10下调炎症反应[肿瘤坏死因子(TNF)- α、IL-1、IL-6、IL-8]以及IL-10本身的合成。我们想知道促炎细胞因子如tnf - α是否可能参与人IL-10合成的调节。tnf - α诱导人外周血单核细胞新生IL-10 mRNA表达呈剂量依赖性，但不诱导IL-10蛋白表达。此外，lps诱导的IL-10基因和蛋白表达被中和抗tnf - α单抗显著抑制。基于这些结果，我们得出结论，tnf - α参与了其拮抗剂IL-10的上调。矛盾的是，通过提高细胞内cAMP水平有效抑制tnf - α表达的药物（iloprost、己酮茶碱、前列腺素E(2)和n6,2 - o -二丁基cAMP）在蛋白质和mRNA水平上增强了内毒素诱导的IL-10合成。为了为分析人IL-10基因的转录调控提供依据，我们分离了人IL-10基因的一个片段，该片段含有1308 bp的5'非编码序列。它在与转录调控相关的区域显示出与小鼠IL-10启动子的显著同源性，包括cAMP响应元件，可以解释cAMP介导的作用。人类序列中缺乏NF-kappa b样结合位点，提示tnf α诱导IL-10基因激活的机制不依赖于NF-kappa b。总之，我们的数据表明，通过诱导IL-10， tnf - α和cAMP升高介质是控制急性炎症反应的负反馈回路的一部分。
It is well established that endotoxin [lipopolysacharide (LPS)] induces pro-inflammatory cytokine production in monocytes, which is followed by secretion of the anti-inflammatory cytokine, IL-10. IL-10 down-regulates inflammatory response [tumor necrosis factor (TNF)-alpha, IL-1, IL-6, IL-8] as well as IL-10 synthesis itself. We wondered whether pro-inflammatory cytokines such as TNF-alpha may be involved in the regulation of human IL-10 synthesis. TNF-alpha induced de novo IL-10 mRNA expression in a dose-dependent manner but no IL-10 protein in human peripheral blood mononuclear cells. Furthermore, LPS-induced IL-10 gene and protein expression was significantly inhibited by neutralizing anti-TNF-alpha mAb. On the basis of these results, we conclude that TNF-alpha is involved in the up-regulation of its antagonist IL-10. Paradoxically, drugs that effectively inhibit expression of TNF-alpha via the elevation of intracellular cAMP level (iloprost, pentoxifylline, prostaglandin E(2) and N6,2-O-dibutyryl cAMP) augmented the endotoxin-induced IL-10 synthesis at both protein and mRNA levels. In order to provide a basis for the analysis of the transcriptional regulation of the human IL-10 gene, we isolated a fragment of the human IL-10 gene containing 1308 bp of the 5' non-coding sequence. It shows remarkable homology to the mouse IL-10 promoter in regions that have been associated with transcriptional regulation, including a cAMP responsive element which could explain the cAMP-mediated effects. The lack of a NF-kappa B-like binding site in the human sequence suggests a NF-kappa B-independent mechanism of TNF-alpha-induced IL-10 gene activation. In summary, our data demonstrate that TNF-alpha and cAMP elevating mediators, via induction of IL-10, are part of a negative feedback circuit that controls acute inflammatory response.