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 poorly defined. Evidence for altered IFN-gamma responses and increased monocyte cyclic AMP phosphodiesterase (PDE) activity in atopic dermatitis (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 peripheral 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. Anti-IFN-gamma was used as control. PDE activity was measured by radioenzyme assay using 1 microM cyclic AMP as final substrate concentration. IFN-gamma caused a dose-dependent increase in PDE activity of normal monocytes and the effect was neutralized by anti-IFN-gamma. By contrast, in atopic monocytes, PDE activity was not affected by IFN-gamma at low dose, while at concentrations greater than 200 U/ml, it significantly reduced phosphodiesterase activity. IFN-gamma of PDE activity may alter normal monocyte functions by decreasing cyclic AMP levels. Paradoxical 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 normalize immune function and could account for recent reports of therapeutic efficacy of IFN-gamma in AD.
Li
S H
SH
Department of Dermatology, Oregon Health Sciences University, School of Medicine, Portland 97201.
Chan
S C
SC
Kramer
S M
SM
Hanifin
J M
JM
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000187:drug effects*; D000242:Cyclic AMP / Q000097:blood; D003876:Dermatitis, Atopic / Q000097:blood / Q000201:enzymology* / Q000628:therapy; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D007962:Leukocytes / Q000187:drug effects* / Q000201:enzymology; D009000:Monocytes / Q000187:drug effects*; D012016:Reference Values
D007371:Interferon-gamma; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases