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The Role of Nuclear Factor B in Tumor Necrosis Factor-Regulated Transcription of the Human µ-Opioid Receptor Gene

Department of Pharmacology and Toxicology, University of Magdeburg, Magdeburg, Germany

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 µ-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-B 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-B also mediates up-regulation of µ-opioid receptors in neuronal cells stimulated with tumor necrosis factor. Among six putative nuclear factor-B binding sites on the µ-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 µ-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.

Address correspondence to: Jürgen Kraus, Department of Pharmacology and Toxicology, University of Magdeburg, 44 Leipziger Strasse, 39120 Magdeburg, Germany. E-mail juergen.kraus{at}medizin.uni-magdeburg.de

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