IN-VITRO DOWN-REGULATION OF ANTIGEN-INDUCED IL-5 GENE-EXPRESSION AND PROTEIN-PRODUCTION BY CAMP-SPECIFIC PHOSPHODIESTERASE TYPE-4 INHIBITOR

The effects of cAMP-elevating agents on antigen-induced IL-5 (interleu kin-5) messenger RNA expression and protein production were examined i n vitro in an antigen-driven system of splenocytes from ovalbumin sens itized BALB/c mice. IL-5 production was inhibited by rolipram, a type 4 phosphodiesterase (PDE4) inhibitor, dose-dependently (maximally at 1 0(-5) M) and by dibutyryl-cAMP (db-cAMP)(3 x 10(-4) M), but not by the type 3 and type 5 PDE inhibitors milrinone and zaprinast (10(-5) M), respectively. Forskolin (10(-5) M), an adenylate cyclase activator, wa s noninhibitory alone but potentiated inhibition by rolipram. Inhibiti on was associated with a decrease in IL-5 mRNA expression. Cycloheximi de 10(-6) M and actinomycin 2 mu g/ml abolished IL-5 production and mR NA expression. We conclude that in splenocytes from sensitized mice, I L-5 production and mRNA expression depend on antigen stimulation. The time course-pc IL-5 protein production is closely related to IL-5 mRNA expression and depends on de novo protein synthesis. db-cAMP and a se lective PDE4 inhibitor, alone or in combination with forskolin, are th e only cAMP-elevating agents that dose dependently inhibited antigen-i nduced IL-5 mRNA expression and protein production. These results are in agreement with in vivo inhibition by a selective PDE4 inhibitor of antigen-induced pulmonary eosinophil infiltration and IL-5 production in sensitized mice, and they suggest that PDE4 inhibitors have potenti al for treating respiratory allergy.