The pathophysiology of atopic dermatitis (AD) is characterized by inflammatory hypersensitivity, altered immunological responses and pharmacophysiological aberrancies. The condition has a genetic basis and the basic defect is carried by hematopoietic cells which travel through the circulation to infiltrate skin and respiratory tissues. Some or all of these cells have abnormally active cyclic AMP-phosphodiesterase (PDE) isoforms. Though the etiology of AD is not entirely clear, the increased PDE activity is present at birth in cord blood mononuclear cells, well before any clinical evidence of disease appears. Our recent studies have demonstrated that a characteristic high activity Type IV PDE isoform present in blood monocytes is associated with increased spontaneous PGE2 and lL-10 secretion and that these endogenous regulatory mediators inhibit production of interferon gamma (IFN-y) by T helper type 1 (Th1) cells. Recent preliminary studies indicate that the monocyte mediators PGE2 and lL-10 not only inhibit Th1, but directly stimulate Th2 and that the atopic T cells are more responsive. Specific Type IV PDE inhibitors reduce PGE2, IL-10 and IL-4 production in AD peripheral blood mononuclear cells (PBMC) to normal levels. We hypothesize that a PDE abnormality resides in atopic T cells, as well as in monocytes, causing increased lL-4 expression in response to the monocyte factors. We predict that in atopic dermatitis: 1) Monocyte factors IL-1O and PGE2 cause a shift in Th1/Th2 equilibrium toward Th2, accounting for such AD features as increased IgE production, decreased cell mediated immunity and inflammatory hyperreactivity, and: 2) both the increased monocyte PGE2 and IL-1O production and the increased T cell lL-4 responses result from abnormal PDE hydrolysis of cyclic AMP. The proposed study will focus upon the effects monocyte PGE2 and lL-1O have on T cells and the characteristics of atopic T cell responses: 1) To compare the effects of lL-1O and PGE2 on atopic and normal peripheral blood T cells: a) effects on cytokine production, especially IL-4 and IFN-y; b) assessment of activation responsive lL-4 gene DNA-binding proteins by gel shift assay; c) assessing mRNA transcriptional responses in cultured cells. 2) To study the relationship between abnormal PDE and lL-4 expression: a) the effect of selective PDE inhibitors on IL-4 production; b) inhibitor effects on lL-4 promotor-binding proteins.
|Effective start/end date||9/30/95 → 8/31/98|
- National Institutes of Health
- National Institutes of Health: $98,996.00
- National Institutes of Health: $107,797.00
Phosphoric Diester Hydrolases
Type 4 Cyclic Nucleotide Phosphodiesterase