Regulation of mu-opioid receptor gene transcription by interleukin-4 and influence of an allelic variation within a STAT6 transcription factor binding site

J Biol Chem. 2001 Nov 23;276(47):43901-8. doi: 10.1074/jbc.M107543200. Epub 2001 Sep 25.

Abstract

Morphine and the endogenous opioid peptide beta-endorphin exert neuromodulatory as well as immunomodulatory effects, which are transduced by mu-opioid receptors. In this report we show that stimulation with interleukin-4 induces mu-opioid receptor transcripts in human primary blood cells (T cells and polymorphonuclear leukocytes), immune cell lines (Raji, U-937, and HMEC-1), and dendritic cells. In nonstimulated immune cells this gene is silent. In addition, mu receptor transcription is up-regulated by interleukin-4 in cultures of primary rat neurons. Transient transfection experiments in Raji and SH SY5Y neuronal cells with human and rat reporter gene constructs linked the interleukin-4 effect directly to cis-active mu receptor promoter elements located at nucleotide -997 on the human gene and nucleotide -727 on the rat gene. The interleukin-4 response elements function orientation independently. They bind STAT6 transcription factors as shown by electrophoretic mobility shift assays. In the human gene, a single nucleotide polymorphism within the interleukin-4 response element reduces the trans-activating potential of this element by 50%, which may affect the phenotype of persons carrying this variation. These findings provide a molecular basis for understanding bidirectional interactions between the opioid system and the immune system.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles*
  • Base Sequence
  • Binding Sites
  • Cell Line
  • Cerebral Cortex / cytology
  • Cerebral Cortex / metabolism
  • DNA Primers
  • Gene Expression Regulation / drug effects*
  • Genetic Variation*
  • Humans
  • Interleukin-4 / pharmacology*
  • Neurons / metabolism
  • Polymorphism, Single Nucleotide
  • Promoter Regions, Genetic
  • Receptors, Opioid, mu / genetics*
  • STAT6 Transcription Factor
  • Trans-Activators / genetics*
  • Trans-Activators / metabolism
  • Transcription, Genetic / drug effects*

Substances

  • DNA Primers
  • Receptors, Opioid, mu
  • STAT6 Transcription Factor
  • STAT6 protein, human
  • Trans-Activators
  • Interleukin-4