title: JAK-STAT1/3-induced expression of signal sequence-encoding proopiomelanocortin mRNA in lymphocytes reduces inflammatory pain in rats.
abstract: BACKGROUND
  Proopiomelanocortin (POMC)-derived beta-endorphin1-31 from immune cells can inhibit inflammatory pain. Here we investigated cytokine signaling pathways regulating POMC gene expression and beta-endorphin production in lymphocytes to augment such analgesic effects.
  
  
  RESULTS
  Interleukin-4 dose-dependently elevated POMC mRNA expression in naïve lymph node-derived cells in vitro, as determined by real-time PCR. This effect was neutralized by janus kinase (JAK) inhibitors. Transfection of Signal Transducer and Activator of Transcription (STAT) 1/3 but not of STAT6 decoy oligonucleotides abolished interleukin-4 induced POMC gene expression. STAT3 was phosphorylated in in vitro interleukin-4 stimulated lymphocytes and in lymph nodes draining inflamed paws in vivo. Cellular beta-endorphin increased after combined stimulation with interleukin-4 and concanavalin A. Consistently, in vivo reduction of inflammatory pain by passively transferred T cells improved significantly when donor cells were pretreated with interleukin-4 plus concanavalin A. This effect was blocked by naloxone-methiodide.
  
  
  CONCLUSIONS
  Interleukin-4 can amplify endogenous opioid peptide expression mediated by JAK-STAT1/3 activation in mitogen-activated lymphocytes. Transfer of these cells leads to inhibition of inflammatory pain via activation of peripheral opioid receptors.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Charité Campus Benjamin Franklin, Freie Universität Berlin, Hindenburgdamm 30, 12200, Berlin, Germany. melanie.busch@charite.de
authors.forename: Melanie
authors.initials: M
authors.lastname: Busch-Dienstfertig
authors.forename: Dominika
authors.initials: D
authors.lastname: Labuz
authors.forename: Theresa
authors.initials: T
authors.lastname: Wolfram
authors.forename: Nicole N
authors.initials: NN
authors.lastname: Vogel
authors.forename: Christoph
authors.initials: C
authors.lastname: Stein
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003208:Concanavalin A / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism*; D015847:Interleukin-4 / Q000494:pharmacology / Q000627:therapeutic use; D053616:Janus Kinase 3 / Q000235:genetics / Q000378:metabolism*; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D009270:Naloxone / Q000031:analogs & derivatives / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy / Q000378:metabolism*; D011333:Pro-Opiomelanocortin / Q000235:genetics*; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D012333:RNA, Messenger; D051381:Rats; D017208:Rats, Wistar; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: D000644:Quaternary Ammonium Compounds; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D003208:Concanavalin A; D015847:Interleukin-4; D009270:Naloxone; D011333:Pro-Opiomelanocortin; C041269:N-methylnaloxone; D053616:Janus Kinase 3