Studies on the modulation of phosphodiesterase activity in human T lymphocytes

My experiments confirmed that both PDE inhibitors and glucocorticoids (GC) inhibited proliferation of peripheral blood mononuclear cells (PBMC). GCs were more effective in inhibiting proliferation of PBMC from severely atopic persons when compared to their counterparts with mild symptoms but PDE inhibitors were equally potent in PBMC from both atopic and nonatopic donors. Secretion of interleukin (IL)-4 and IL-5 by Th2 cells and tumour necrosis factor (TNF)-α and IL-10 by PBMC was also concentration dependently suppressed by GCs and PDE inhibitors. GCs inhibited secretion of cytokines and proliferation to a greater extent in PBMCs than Th2 cells and cells from asymptomatic than symptomatic donors, respectively. PDE inhibitors and GCs both suppressed TNF-α more than IL-10 secretion. Finally, PDE inhibitors were more potent in decreasing IL-10 and TNF-α secretion by PBMC from atopic than nonatopic donors.When PDE activity was assessed directly, I found a significant increase in Th2 cell lines and CD4+ T cells from asymptomatic asthmatics. It was also elevated in CD4+ T cells from nonatopic controls that had been activated in vitro with IL-2 or phytohaemag-glutinin. Finally, there was a trend towards elevation in PDE activity in PBMC from asthmatic patients after bronchial allergen challenge in CD4+ T cells from midseasonal allergic rhinitis patients.In conclusion, I have confirmed that both PDE inhibitors and GCs suppress proliferation and cytokine secretion. Since GCs are much more potent than PDE inhibitors in suppressing T cell function and only moderately reduce PDE activity, it is evident that their effects are mediated at most partially through inhibition of PDE activity. The complex pattern of effect of GCs on PDE activity indicates that a number of pathways, both direct and indirect, may be involved. Clearly, more work is necessary to fully elucidate the mechanisms that play a role in GC inhibition of PDE activity.