CYTOKINE PRODUCTION BY PHYTOHEMAGGLUTININ-STIMULATED HUMAN BLOOD-CELLS - EFFECTS OF CORTICOSTEROIDS, T-CELL IMMUNOSUPPRESSANTS AND PHOSPHODIESTERASE-IV INHIBITORS

The ability of dexamethasone and prednisolone (corticosteroids), FK506 and cyclosporin A (T cell immunosuppressants), and of nitraquazone and rolipram (phosphodiesterase IV inhibitors) to inhibit cytokine production by stimulated human blood was investigated. Heparinized human blood obtained from normal healthy volunteers was stimulated with phytohemagglutinin (PHA) in the presence or absence of drug. After different incubation times, supernatant levels of interleukin (IL)-2, IL-5, granulocyte-macrophage colony stimulating factor (GM-CSF) and interferon gamma (IFN-gamma) were quantified by ELISA. Dexamethasone strongly inhibited the production of IL-5 (IC50 = 0.004 mu M), was less potent against IL-2 and IFN-gamma (IC50 = 0.02-0.05 mu M) and showed a relatively weak effect against GM-CSF (IC50 = 0.6 mu M) Similarly prednisolone potently suppressed IL-5 generation (IC50 = 0.05 mu M), displayed a more modest activity on IL-2 and IFN-gamma (IC50 = 0.2-0.3 mu M) and exerted only partial effects (43% inhibition at 1 mu M) on GM-CSF. FK506 strongly suppressed the production of IL-2 (IC50 = 0.01 mu M) and GM-CSF (IC50 = 0.03 mu M), but was inactive (<30% inhibition at 1 mu M) against IL-5 and IFN-gamma. Similarly, cyclosporin A reduced the generation of IL-2 (IC50 = 0.4 mu M) and GM-CSF (IC50 = 0.6 mu M) while barely affecting the other two cytokines. Nitraquazone and rolipram were most active in reducing the production of IL-5 (IC50 = 0.8 and 1.3 mu M, respectively), while their potency against IL-2, GM-CSF and IFN-gamma was 3-6 times lower, with IC50'S between 2.4 and 8.0 mu M. These data indicate that corticosteroids, T cell immuno-suppressants and phosphodiesterase IV inhibitors affect cytokine production by PHA-stimulated human blood cells in a differential and ''pharmacotypical'' manner.