IN-VITRO DIFFERENTIAL-EFFECTS OF THE ANTIGLUCOCORTICOID RU486 ON THE RELEASE OF LYMPHOKINES FROM MITOGEN-ACTIVATED NORMAL HUMAN-LYMPHOCYTES

The synthetic antiglucocorticoid RU486 has multiple effects on the imm une system. We have recently reported that RU486 suppresses normal lym phocyte proliferation and downregulates interleukin-2 receptors (IL-2R ) by decreasing the accumulation of the beta-chain IL-2R mRNA in norma l human lymphocytes in culture. To further explore the mechanism of th e immunoregulatory actions of RU486, in the present study, we investig ated the effects of this molecule on the release of lymphokines from p hytohemagglutinin (PHA)-activated normal human peripheral blood lympho cytes (NPBL) in culture. We have found that RU486 differentially regul ates the release of lymphokines from PHA-activated NPB lymphocytes. Sp ecifically, RU486 (at concentrations of 1-100 nM) exerts pure antagoni st actions by almost completely reversing the inhibitory effects of th e glucocorticoid dexamethasone (Dex) on the release of monocyte/macrop hages-derived lymphokines, such as IL-1, IL-6, IL-8 and tumor necrosis factor-alpha (TNF-alpha). Dex decreased in a dose-dependent manner th e release of the above four lymphokines, with an ID50 of 0.9 +/- 0.1, 4.76 +/- 0.4, 9.8 +/- 1.8, and 1.16 +/- 0.2 nM for IL-1, IL-6, IL-8 an d TNF-alpha, respectively. Conversely, RU486 exhibits both agonist and antagonist effects on the release of T-lymphocyte-derived lymphokines . RU486 given alone, exerts agonist/glucocorticoid effects, by decreas ing in a dose-dependent manner the release of IL-2 and -3. The maximal inhibitory effect of RU486 was observed at 10 nM and was 64.5 +/- 4.3 % of the control value, (n = 6, P < 0.02) for IL-2 and 59.2 +/- 6.3% ( n = 6, P < 0.2) for IL-3. The ID50 of RU486 for the release of IL-2 an d -3 were 14.6 +/- 2.0 and 11.6 +/- 1.9 nM, respectively, i.e. almost similar with those of Dex. Interestingly, when high doses of RU486 (1 mu M) were combined with Dex RU486 exhibited antagonist actions by sig nificantly counteracting the inhibitory effects of Dex on IL-2 and -3 release. In conclusion, the antiglucocorticoid RU486 exhibits complex regulatory actions on lymphokine secretion, dependent upon the type of the lymphokine-producing cell. A pure antagonist effect was observed on the release of monocyte-derived IL-1, IL-6, IL-8 and TNF-alpha. How ever, when RU486 was given alone it acted as a glucocorticoid agonist on the secretion of T-lymphocyte-derived IL-2 and -3, while combined w ith the agonist (Dex) it exhibits antagonist effects on the release of the above lymphokines. This molecule still remains unexplored as an i mmunoregulatory agent. Further studies are needed in order to assess i ts relevance on pharmacological intervention in the immune system.