Regulation of mu-opioid receptor gene transcription by interleukin-4 and influence of an allelic variation within a STAT6 transcription factor binding site.
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.
Kraus
J
J
Department of Pharmacology, University of Magdeburg, 44 Leipziger Strasse, 39120 Magdeburg, Germany. juergen.kraus@medizin.uni-magdeburg.de
Borner
C
C
Giannini
E
E
Hickfang
K
K
Braun
H
H
Mayer
P
P
Hoehe
M R
MR
Ambrosch
A
A
Konig
W
W
Hollt
V
V
D000483:Alleles; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism; D017931:DNA Primers; D005786:Gene Expression Regulation / Q000187:drug effects*; D014644:Genetic Variation; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology*; D009474:Neurons / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D017450:Receptors, Opioid, mu / Q000235:genetics*; D050800:STAT6 Transcription Factor; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*
D017931:DNA Primers; D017450:Receptors, Opioid, mu; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015534:Trans-Activators; D015847:Interleukin-4