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O Kaminuma, A Mori, M Suko, H Kikkawa, K Ikezawa and H Okudaira
Department of Medicine and Physical Therapy, University of Tokyo, Faculty of Medicine, Japan.
The effect of T-440, a selective type IV phosphodiesterase inhibitor, on cytokine production by peripheral blood mononuclear cells (PBMC) of atopic asthmatics was investigated. T-440 suppressed allergen-induced interleukin (IL)-5 production with a high potency (IC50 = 0.039 microgram/ml) and allergen-induced proliferation of PBMC (IC50 = 0.30 microgram/ml). T-440 also suppressed IL-2, IL-4 and IL-5 production by concanavalin A-activated PBMC in concentration-dependent manner. The IC50 values for the suppression of cytokine synthesis were 0.11 microgram/ml for IL-2, 0.57 microgram/ml for IL-5 and 7.7 micrograms/ml for IL-4. cAMP-elevating agents, such as PGE2, forskolin and dibutyryl cAMP, suppressed IL-2, IL-4 and IL-5 production by concanavalin A- stimulated PBMC in a manner similar to that of T-440. T-440 inhibited cAMP-phosphodiesterase activity and raised the intracellular cAMP level of PBMC in a concentration-dependent manner, suggesting that the increase of intracellular cAMP caused by T-440 results in the reduction of cytokine production. We conclude that T-440 suppressed cytokine production by peripheral T lymphocytes via the protein kinase A pathway and may be an effective modality to treat atopic diseases associated with eosinophilic inflammation.
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