Phosphodiesterase 4 inhibitors prevent cytokine secretion by T lymphocytes by inhibiting nuclear factor-kappaB and nuclear factor of activated T cells activation.
Blockade of phosphodiesterase 4 with rolipram reduced the production of tumor necrosis factor (TNF)-alpha, interleukin (IL)-5, IL-10, and IL-2 but poorly inhibited cell proliferation and interferon-gamma (IFN-gamma) production by activated human T cells. Addition of dibutyryl cAMP mimicked rolipram inhibitions on proliferation, IL-2, TNF-alpha, and IFN-gamma but not on IL-10 or IL-5 production. Moreover, the inhibitory effects of rolipram on proliferation, IFN-gamma, and TNF-alpha but not of IL-10 production can be prevented by a specific protein kinase A inhibitor. Rolipram and pentoxifylline, a nonspecific phosphodiesterase inhibitor, decreased transcription of IL-2 and TNF-alpha promoters in transiently transfected normal T cells. Moreover, they inhibited the activation of nuclear factor-kappaB (NF-kappaB) and nuclear factor of activated T cells (NFAT) and stimulated activator protein-1 (AP-1) and cAMP response element-binding proteins (CREBs). In contrast, dibutyryl cAMP inhibited NF-kappaB but not NFAT activation. Thus, our data indicate that blockade of phosphodiesterase 4 regulates transcription of a particular cytokine through inhibition of NF-kappaB and NFAT, and stimulation of AP-1 and CREB.
Jimenez
J L
JL
Centro de Biología, Consejo Superior de Investigaciones Cientificas, Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain.
Punzón
C
C
Navarro
J
J
Muñoz-Fernández
M A
MA
Fresno
M
M
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D001711:Biotransformation / Q000187:drug effects; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors*; D004586:Electrophoresis; D006801:Humans; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors*; D014158:Transcription, Genetic / Q000187:drug effects
D016207:Cytokines; D004268:DNA-Binding Proteins; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010726:Phosphodiesterase Inhibitors; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4