The role of nuclear factor κB in tumor necrosis factor-regulated transcription of the human μ-opioid receptor gene
The role of nuclear factor κB in tumor necrosis factor-regulated transcription of the human μ-opioid receptor gene
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DOI：
10.1124/mol.64.4.876
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发表时间：
2003-10-01
影响因子：
3.6
通讯作者：
Höllt, V
中科院分区：
文献类型：
--
作者：
Kraus, J;Börner, C;Höllt, V
阿片类药物及其受体在神经系统和免疫系统之间的串扰中起着关键作用。例如，内源性阿片系统在炎症期间被激活，作为一种生理反馈机制来减轻炎症性疼痛。在此，我们报道了在原代人T淋巴细胞、Raji B细胞、U937单核细胞、原代人多形核白细胞和成熟树突状细胞中，促炎细胞因子肿瘤坏死因子诱导了mu-阿片受体基因的转录。该基因在免疫细胞中的转录诱导是通过肿瘤坏死因子受体2型介导的。利用诱饵寡核苷酸在体内选择性破坏可能涉及的转录因子，核因子- kappab被确定为在免疫细胞中诱导该基因的因子，而激活蛋白-1被发现不参与。在受肿瘤坏死因子刺激的神经细胞中，核因子κ b也可介导多阿片受体的上调。通过报告基因构建的转染实验、电泳迁移率转移实验以及与诱饵寡核苷酸的体内结合研究，在6个假定的核因子- kappab在μ -阿片受体基因启动子上的结合位点中，鉴定了3个位于nt -2174、-557和-207的顺式活性元件。-557元件内的等位基因变异显著降低了其反式激活效力，这可能影响携带该突变的人对mu-阿片受体基因的调节。本研究提示肿瘤坏死因子在阿片介导的神经元和免疫细胞过程中具有调节作用，并可能影响炎症诱导镇痛复合物。
Opioids and their receptors are key players in a cross-talk between the nervous and immune systems. For example, the endogenous opioid system is activated during inflammation as a physiological feedback mechanism to attenuate inflammatory pain. Herein, we report that in primary human T lymphocytes, Raji B cells, U937 monocytes, primary human polymorphonuclear leukocytes, and mature dendritic cells, the proinflammatory cytokine tumor necrosis factor induced mu-opioid receptor gene transcription. Transcriptional induction of the gene in immune cells was mediated via tumor necrosis factor receptor type 2. Using selective in vivo disruption of possibly involved transcription factors with decoy oligonucleotides, nuclear factor-kappaB was identified as the factor responsible for induction of the gene in immune cells, whereas activator protein-1 was found to be uninvolved. Nuclear factor-kappaB also mediates up-regulation of mu-opioid receptors in neuronal cells stimulated with tumor necrosis factor. Among six putative nuclear factor-kappaB binding sites on the mu-opioid receptor gene promoter, three cis-active elements at nt -2174, -557, and -207 were identified using transfection experiments of reporter gene constructs, electrophoretic mobility shift assays, and in vivo binding studies with decoy oligonucleotides. An allelic variation within the -557 element significantly reduced its trans-activating potency, which may affect regulation of the mu-opioid receptor gene in persons carrying this mutation. This study suggests a regulatory function of tumor necrosis factor in opioid-mediated processes in neuronal and immune cells, with possible impact on the complex of inflammation-induced analgesia.