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 (interleukin-5) messenger RNA expression and protein production were examined in vitro in an antigen-driven system of splenocytes from ovalbumin sensitized BALB/c mice. IL-5 production was inhibited by rolipram, a type 4 phosphodiesterase (PDE4) inhibitor, dose-dependently (maximally at 10(-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, was noninhibitory alone but potentiated inhibition by rolipram. Inhibition was associated with a decrease in IL-5 mRNA expression. Cycloheximide 10(-6) M and actinomycin 2 micrograms/ml abolished IL-5 production and mRNA expression. We conclude that in splenocytes from sensitized mice, IL-5 production and mRNA expression depend on antigen stimulation. The time course of IL-5 protein production is closely related to IL-5 mRNA expression and depends on de novo protein synthesis. db-cAMP and a selective PDE4 inhibitor, alone or in combination with forskolin, are the only cAMP-elevating agents that dose-dependently inhibited antigen-induced 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 potential for treating respiratory allergy.
Foissier
L
L
Department of Respiratory Pharmacology, Servier Research Institute, Suresnes, France.
Lonchampt
M
M
Cogé
F
F
Canet
E
E
D015105:3',5'-Cyclic-AMP Phosphodiesterases; D000818:Animals; D000941:Antigens / Q000276:immunology*; D001249:Asthma / Q000188:drug therapy; D000242:Cyclic AMP / Q000502:physiology*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D015536:Down-Regulation; D005786:Gene Expression Regulation / Q000187:drug effects; D015848:Interleukin-5 / Q000235:genetics*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D010047:Ovalbumin / Q000276:immunology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000502:physiology*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D020889:Rolipram; D013154:Spleen / Q000166:cytology
D000941:Antigens; D015848:Interleukin-5; D019384:Nucleic Acid Synthesis Inhibitors; D010726:Phosphodiesterase Inhibitors; D011500:Protein Synthesis Inhibitors; D011760:Pyrrolidinones; D012333:RNA, Messenger; D003609:Dactinomycin; D010047:Ovalbumin; D003513:Cycloheximide; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram