Journal
MOLECULAR PAIN
Volume 8, Issue -, Pages -Publisher
SAGE PUBLICATIONS INC
DOI: 10.1186/1744-8069-8-83
Keywords
Pain; Inflammation; Opioid peptides; Immune cells; Neuro-immune interactions; Cytokine signaling
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Funding
- Bundesministerium fur Bildung und Forschung (BMBF) [ImmunoPain 01 EC 1004 C]
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Background: Proopiomelanocortin (POMC)-derived beta-endorphin(1-31) 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 naive 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. Conclusion: 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.
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