ROLE OF OPIOID-PEPTIDES IN THE REGULATION OF CYTOKINE PRODUCTION BY MURINE CD4(-CELLS() T)

The presence of the opioid peptides alpha- and P-endorphin (-End) but not methionine enkephalin (Met-enk) in in vitro cultures of purified C D4(+) T cells, stimulated with concanavalin A in the presence of irrad iated spleen cells, resulted in a threefold stimulation of IL-2, IL-4, and IFN-gamma production. The stimulating effect was dependent on the concentration of the peptides and reached optimal values in the dose range from 10(-12) to 10(-10) M. Similar results were obtained when pu rified CD4(+) T cells were stimulated with immobilized anti-CD3, indic ating a direct effect of opioid peptides on CD4(+) T cells. Moreover, in this system a twofold enhancement of IL-6, but not IL-1, secretion was observed. These stimulatory effects were not mediated through opio id receptors since the peptide fragment beta-End(6-31) that lacks the N-terminal opioid receptor binding part was still stimulatory. This is in agreement with our finding that beta-End did not affect cAMP, as d escribed for the triggering of classical opioid receptors. Experiments undertaken to reveal the mechanism of action of opioid peptides sugge st an overall enhancement of lymphokine production: (1) enhancement of IL-4 production occurred also in the presence of excess IL-2; and (2) neither IL-1 receptor-antagonizing protein nor anti-IL-6 were capable to abrogate the stimulatory effect on IL-2 and IL-4 production. Final ly, the presence and activity of opioid receptors in cultures of CD4() T cells were substantiated by the fact that the opioid receptor anta gonist naloxone by itself enhanced cytokine synthesis, which points to the endogenous production by lymphocytes of down-regulating opioid pe ptides. (C) 1994 Academic Press, Inc.