ROLE OF ENDOGENOUS PROENKEPHALIN A-DERIVED PEPTIDES IN HUMAN T-CELL PROLIFERATION AND MONOCYTE IL-6 PRODUCTION

In this paper, we describe that met-enkephalin and/or enkephalin-conta ining intermediary peptides of the prohormone pro-enkephalin A are pro duced and secreted by human peripheral blood T cells and monocytes. Th e peptides are produced after stimulation with the mitogenic monoclona l antibodies anti-CD2.1/2.2 and anti-CD28. In monocytes, enkephalin sy nthesis was induced by stimulation with lipopolysaccharide. We demonst rate here that these immune cell-derived enkephalins play an important regulatory role in the immune response. By using an anti-sense oligon ucleotide strategy we could block the production of enkephalins. Block ade of the production of met-enkephalin and enkephalin-containing inte rmediary peptides resulted in enhancement of the proliferative T cell response and inhibition of monocyte IL-6 secretion. In vitro reconstit ution of the anti-sense treated cultures with synthetic met-enkephalin or the delta-type specific opioid receptor agonist deltorphin could r everse inhibition of monocyte IL-6 production, suggesting that endogen ous enkephalins act via membrane opioid receptors. In contrast, additi on of met-enkephalin or deltorphin to the anti-sense treated T cell cu ltures did not have any effect on T cell proliferation. (C) 1998 Elsev ier Science B.V.