RT Journal Article
SR Electronic
T1 Preferential Inhibition of T Helper 1, but Not T Helper 2, Cytokines in Vitro by L-826,141 [4-{2-(3,4-Bisdifluromethoxyphenyl)-2-{4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-phenyl]-ethyl}-3-methylpyridine-1-oxide], a Potent and Selective Phosphodiesterase 4 Inhibitor
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 752
OP 760
DO 10.1124/jpet.103.064691
VO 310
IS 2
A1 D. Claveau
A1 S. L. Chen
A1 S. O'Keefe
A1 D. M. Zaller
A1 A. Styhler
A1 S. Liu
A1 Z. Huang
A1 D. W. Nicholson
A1 J. A. Mancini
YR 2004
UL http://jpet.aspetjournals.org/content/310/2/752.abstract
AB 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 IC50 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)-α in peripheral blood mononuclear cell and whole blood assays with IC50 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)γ (IC50 values of 0.3-0.9 μM) as well as TNF-α 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 IC35 value of 25 nM and Th1-mediated IFNγ production with an IC30 value of 46 nM. In contrast, L-826,141 had no significant inhibitory effect (IC30 value > 2.5 μM) 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 American Society for Pharmacology and Experimental Therapeutics