L-826,141 [4-{2-(3,4-bis-difluromethoxyphenyl)-2-{4-(1,1,1, 3,3,3-hexafluoro-2-hydroxypropan-2-yl)-phenyl]-ethyl}-3-methylpyridine-1-oxide] is a selective and potent inhibitor of phosphodiesterase 4 (PDE4) with an IC 50 value of 0.26 to 2.4 nM for inhibition of the catalytic activity of PDE4A, B, C, and D. The cAMP elevation that can be maintained by PDE4 inhibitors attenuates the signaling cascades that lead to the production of certain cytokines. In cellular-based assays, L-826,141 transcriptionally down-regulates production of tumor necrosis factor (TNF)-␣ in peripheral blood mononuclear cell and whole blood assays with IC 50 values of 31 and 310 nM, respectively. Profiling the effect of this compound on various cytokines in the signaling cascade attenuated by cAMP elevation demonstrates that L-826,141 is also a potent inhibitor of interleukin (IL)-12, granulocyte macrophage-colony stimulating factor, and interferon (IFN)␥ (IC 50 values of 0.3-0.9 M) as well as TNF-␣ formation. We have also shown that the PDE4 inhibitors rolipram and L-826,141 are potent inhibitors of CD3-plus CD28-stimulated IL-2 production in naive human T cells. To address the effect of PDE4 inhibitors on cytokine release from T helper (Th)1 and Th2 effector cells, we used a well characterized model in which T cells are derived from ovalbumin (323-339)-specific T cell receptor transgenic mice. L-826,141 inhibits Th0-mediated IL-2 production with an IC 35 value of 25 nM and Th1-mediated IFN␥ production with an IC 30 value of 46 nM. In contrast, L-826,141 had no significant inhibitory effect (IC 30 value Ͼ 2.5 M) on Th2 cell-mediated IL-4 nor IL-13 production. Together, these data demonstrate that specific inhibition of PDE4 preferentially blocks the production of Th1 versus Th2 effector cytokines in vitro.The second messenger cAMP and the ensuing signaling cascades have been investigated for more than 50 years (Robison et al., 1968). cAMP is generated enzymatically by the action of adenylate cyclase, and this enzyme is activated after the interaction of various ligands with G protein-coupled receptors (Krupinski et al