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Transcriptional Regulation of the Human µ-Opioid Receptor Gene by Interleukin-6

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

Inflammatory pain is counteracted by a number of physiological processes. For example, opioid receptors, which are present on peripheral terminals of sensory neurons, are activated by endogenous opioids, which are released from immune cells migrating to the inflamed tissue. Earlier data demonstrated that interleukin-6 contributes to such inflammation-induced analgesia. In this report, we demonstrated that interleukin-6 strongly induces µ-opioid receptor mRNA in the human neuroblastoma cell line SH SY5Y, whereas -opioid receptor mRNA levels are not influenced. The mRNA increase in these cells is followed by an increase in µ-opioid receptor-specific binding. Using transcription factor decoy oligonucleotides, direct evidence was provided that the up-regulation of µ-opioid receptor mRNA in intact cells is dependent on the transcription factors signal transducers and activators of transcription 1 (STAT1) and STAT3, whereas other transcription factors, such as activator protein-1, nuclear factor (NF)-B, or NF-interleukin-6 are not involved. STAT1 and STAT3 bound to a site located at nucleotide -1583 on the promoter of the human µ-opioid receptor gene, as shown by transient transfection experiments, electrophoretic mobility shift assays, and transcription factor decoy oligonucleotides. A mutation analysis of the 5'-TTCATGGAA-3' STAT1/3 element (palindrome underlined) was performed to determine nucleotide residues that are necessary for the binding of STAT1 and STAT3. It suggested that only the palindromic half sides and the two adjacent central nucleotides are required. Neither mutation of the nucleotides outside the palindrome nor mutation of the central nucleotide affected STAT1/3 binding.

Address correspondence to: Dr. 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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