Regulation of mu-opioid receptor gene transcription by interleukin-4 and influence of an allelic variation within a STAT6 transcription factor binding site
J. Kraus et al., 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, 276(47), 2001, pp. 43901-43908
Morphine and the endogenous opioid peptide P-endorphin exert neuromodulator
y as well as immunomodulatory effects, which are transduced by mu -opioid r
eceptors. In this report we show that stimulation with interleukin-4 induce
s Ik-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 cu
ltures of primary rat neurons. Transient transfection experiments in Raji a
nd SH SY5Y neuronal cells with human and rat reporter gene constructs linke
d the interleukin-4 effect directly to cis-active mu receptor promoter elem
ents located at nucleotide -997 on the human gene and nucleotide -727 on th
e rat gene. The interleukin-4 response elements function orientation indepe
ndently. 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 pote
ntial of this element by 50%, which may affect the phenotype of persons car
rying this variation. These findings provide a molecular basis for understa
nding bidirectional interactions between the opioid system and the immune s
ystem.