Altered prostaglandin E₂ regulation of cytokine production in atopic dermatitis

The monocyte-derived inflammatory mediator, prostaglandin E₂ (PGE₂), can reduce IFN-γ production, and this in turn may relate to IL-4 up-regulation of IgE synthesis and impaired delayed hypersensitivity in atopy. These abnormalities may relate to the cyclic nucleotide dysregulation in atopic dermatitis (AD), where monocyte cyclic AMP-phosphodiesterase (PDE) activity is increased and the consequent reduction in cAMP levels allows increased inflammatory responsiveness. In this study, we assessed the relationship between PGE₂ and IFN-γ production along with abnormal PDE activity in AD monocytes. Blood mononuclear leukocytes (MNL) from normal and AD donors were cultured for 24 hours, and supernatants were assayed for PGE₂ and IFN-γ by RIA. Spontaneous PGE₂, but not leukotriene C₄ release, was significantly increased in AD MNL (p < 0.05), although IFN-γ levels were reduced (p < 0.05). In contrast, purified AD T cells, after removal of PGE₂-producing monocytes, produced levels of IFN-γ significantly higher than in normal T cell cultures. Inhibition of PGE₂ synthesis by indomethacin caused increased IFN-γ production by MNL cultures. We noted a strong negative correlation (r = 0.77) between PDE activity and IFN-γ production in MNL cultures. We speculate that abnormal cyclic nucleotide metabolism caused by increased PDE activity may allow elevated levels of PGE₂ production by AD monocytes. This study demonstrates a regulatory interaction between monocytes and T cells in AD and suggests that PGE₂ may be an extracellular messenger between these cells to modulate IFN-θ production.