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Vol. 299, Issue 2, 753-759, November 2001

Phosphodiesterase 4 Inhibitors Prevent Cytokine Secretion by T Lymphocytes by Inhibiting Nuclear Factor-kappa B and Nuclear Factor of Activated T Cells Activation

José Luis Jimenez1 , Carmen Punzón1 , Joaquín Navarro, M. Angeles Muñoz-Fernández and Manuel Fresno

Centro de Biología Molecular, Consejo Superior de Investigaciones Cientificas, Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain (C.P., M.F.); and Department of Immunology, Hospital Universitario Gregorio Marañón, Madrid, Spain (J.L.J., J.N., M.A.M.-F.)

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-kappa B (NF-kappa B) 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-kappa B but not NFAT activation. Thus, our data indicate that blockade of phosphodiesterase 4 regulates transcription of a particular cytokine through inhibition of NF-kappa B and NFAT, and stimulation of AP-1 and CREB.

1 These authors contributed equally to this work.

0022-3565/01/2992-0753$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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