Phosphodiesterase 4 inhibitors prevent cytokine secretion by T lymphocytesby inhibiting nuclear factor-kappa B and nuclear factor of activated T cells activation

Blockade of phosphodiesterase 4 with rolipram reduced the production of tum or necrosis factor (TNF)-alpha, interleukin (IL)-5, IL-10, and IL-2 but poo rly inhibited cell proliferation and interferon-gamma (IFN-gamma) productio n 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 prol iferation, IFN-gamma, and TNF-alpha but not of IL-10 production can be prev ented 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. Moreov er, 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 stimulati on of AP-1 and CREB.