Received for publication June 10, 2004.
Revised September 21, 2004.
Accepted for publication September 21, 2004.

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

Abstract

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 upregulation of µ-opioid receptor mRNA in intact cells is dependent on the transcription factors STAT1 and 3, whereas other transcription factors, such as AP-1, NFB or NF-interleukin-6 are not involved. STAT1 and 3 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 binding of STAT1 and 3. 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.

Key words: Opioid, Jak/Stats, Stat activated transcriptional events, Promoter analysis, Regulation of gene expression

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