MODULATION OF LEUKOCYTE CYCLIC-AMP PHOSPHODIESTERASE ACTIVITY BY RECOMBINANT INTERFERON-GAMMA - EVIDENCE FOR A DIFFERENTIAL EFFECT ON ATOPIC MONOCYTES

Mechanisms of interferon-gamma (IFN-gamma) effects on monocytes are po orly defined. Evidence for altered IFN-gamma responses and increased m onocyte cyclic AMP phosphodiesterase (PDE) activity in atopic dermatit is (AD) suggested a possible relationship. PDE activity in response to IFN-gamma was assessed in normal and atopic monocytes to evaluate the IFN-gamma regulatory role in cell function. Adherence-isolated periph eral blood monocytes were exposed to recombinant human IFN-gamma at 0. 1-300 U/ml in Gey's balanced salt solution for varying time periods. A nti-IFN-gamma was used as control. PDE activity was measured by radioe nzyme assay using 1 muM cyclic AMP as final substrate concentration. I FN-gamma caused a dose-dependent increase in PDE activity of normal mo nocytes and the effect was neutralized by anti-IFN-gamma. By contrast, in atopic monocytes, PDE activity was not affected by IFN-gamma at lo w dose, while at concentrations greater than 200 U/ml, it significantl y reduced phosphodiesterase activity. IFN-gamma of PDE activity may al ter normal monocyte functions by decreasing cyclic AMP levels. Paradox ical PDE unresponsiveness probably reflects maximal PDE activation in atopic monocytes. This elevated PDE activity is inhibited by high IFN- gamma levels. Reduction of atopic monocyte PDE activity may help to no rmalize immune function and could account for recent reports of therap eutic efficacy of IFN-gamma in AD.