Role of endogenous pro-enkephalin A-derived peptides in human T cell proliferation and monocyte IL-6 production.
In this paper, we describe that met-enkephalin and/or enkephalin-containing intermediary peptides of the prohormone pro-enkephalin A are produced and secreted by human peripheral blood T cells and monocytes. The peptides are produced after stimulation with the mitogenic monoclonal antibodies anti-CD2.1/2.2 and anti-CD28. In monocytes, enkephalin synthesis was induced by stimulation with lipopolysaccharide. We demonstrate here that these immune cell-derived enkephalins play an important regulatory role in the immune response. By using an anti-sense oligonucleotide strategy we could block the production of enkephalins. Blockade of the production of met-enkephalin and enkephalin-containing intermediary peptides resulted in enhancement of the proliferative T cell response and inhibition of monocyte IL-6 secretion. In vitro reconstitution of the anti-sense treated cultures with synthetic met-enkephalin or the delta-type specific opioid receptor agonist deltorphin could reverse inhibition of monocyte IL-6 production, suggesting that endogenous enkephalins act via membrane opioid receptors. In contrast, addition of met-enkephalin or deltorphin to the anti-sense treated T cell cultures did not have any effect on T cell proliferation.
Kamphuis
S
S
Department of Immunology, University Hospital for Children and Youth, Het Wilhelmina Kinderziekenhuis, Utrecht, The Netherlands.
Eriksson
F
F
Kavelaars
A
A
Zijlstra
J
J
van de Pol
M
M
Kuis
W
W
Heijnen
C J
CJ
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D004744:Enkephalin, Methionine / Q000494:pharmacology; D004745:Enkephalins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D011498:Protein Precursors / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects*
D000911:Antibodies, Monoclonal; D016207:Cytokines; D004745:Enkephalins; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016376:Oligonucleotides, Antisense; D009842:Oligopeptides; D010455:Peptides; D011498:Protein Precursors; C029992:proenkephalin; C059567:deltorphin; D004744:Enkephalin, Methionine