Preferential inhibition of T helper 1, but not T helper 2, cytokines in vitro by 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], a potent and selective phosphodiesterase 4 inhibitor

被引:80
作者
Claveau, D
Chen, SL
O'Keefe, S
Zaller, DM
Styhler, A
Liu, S
Huang, Z
Nicholson, DW
Mancini, JA
机构
[1] Merck Res Labs, Dept Inflammat Res, Rahway, NJ USA
[2] Merck Frosst Ctr Therapeut Res, Dept Biochem & Mol Biol, Kirkland, PQ, Canada
关键词
D O I
10.1124/jpet.103.064691
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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)-alpha 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)gamma (IC50 values of 0.3-0.9 muM) as well as TNF-alpha 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 IFNgamma production with an IC30 value of 46 nM. In contrast, L-826,141 had no significant inhibitory effect (IC30 value > 2.5 muM) 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.
引用
收藏
页码:752 / 760
页数:9
相关论文
共 44 条
  • [1] Therapy of chronic obstructive pulmonary disease
    Barnes, PJ
    [J]. PHARMACOLOGY & THERAPEUTICS, 2003, 97 (01) : 87 - 94
  • [2] Therapeutic potential of phosphodiesterase-4 and-3 inhibitors in Th1-mediated autoimmune diseases
    Bielekova, B
    Lincoln, A
    McFarland, H
    Martin, R
    [J]. JOURNAL OF IMMUNOLOGY, 2000, 164 (02) : 1117 - 1124
  • [3] EOSINOPHILS EXPRESS INTERLEUKIN-5 AND GRANULOCYTE MACROPHAGE-COLONY-STIMULATING FACTOR MESSENGER-RNA AT SITES OF ALLERGIC INFLAMMATION IN ASTHMATICS
    BROIDE, DH
    PAINE, MM
    FIRESTEIN, GS
    [J]. JOURNAL OF CLINICAL INVESTIGATION, 1992, 90 (04) : 1414 - 1424
  • [4] RESPONSES OF NOD CONGENIC MICE TO A GLUTAMIC-ACID DECARBOXYLASE-DERIVED PEPTIDE
    CHEN, SL
    WHITELEY, PJ
    FREED, DC
    ROTHBARD, JB
    PETERSON, LB
    WICKER, LS
    [J]. JOURNAL OF AUTOIMMUNITY, 1994, 7 (05) : 635 - 641
  • [5] Cilomilast, a selective phosphodiesterase-4 inhibitor for treatment of patients with chronic obstructive pulmonary disease: a randomised, dose-ranging study
    Compton, CH
    Gubb, J
    Nieman, R
    Edelson, J
    Amit, O
    Bakst, A
    Ayres, JG
    Creemers, JPHM
    Schultze-Werninghaus, G
    Brambilla, C
    Barnes, NC
    [J]. LANCET, 2001, 358 (9278) : 265 - 270
  • [6] Cyclic AMP-specific PDE4 phosphodiesterases as critical components of cyclic AMP signaling
    Conti, M
    Richter, W
    Mehats, C
    Livera, G
    Park, JY
    Jin, C
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (08) : 5493 - 5496
  • [7] ADENYLYL CYCLASES AND THE INTERACTION BETWEEN CALCIUM AND CAMP SIGNALING
    COOPER, DMF
    MONS, N
    KARPEN, JW
    [J]. NATURE, 1995, 374 (6521) : 421 - 424
  • [8] Molecular docking of competitive phosphodiesterase inhibitors
    Dym, O
    Xenarios, I
    Ke, HM
    Colicelli, J
    [J]. MOLECULAR PHARMACOLOGY, 2002, 61 (01) : 20 - 25
  • [9] Foissier L, 1996, J PHARMACOL EXP THER, V278, P1484
  • [10] Griswold DE, 1998, J PHARMACOL EXP THER, V287, P705