Souness J E, Houghton C, Sardar N, Withnall M T
Rhône-Poulenc Rorer Central Research, Dagenham Research Centre, Essex, UK.
Biochem Pharmacol. 1999 Sep 15;58(6):991-9. doi: 10.1016/s0006-2952(99)00176-8.
We investigated the suppressive effects of rolipram, RP 73401 (piclamilast), and other structurally diverse inhibitors of adenosine 3'5'-cyclic monophosphate (cAMP)-specific phosphodiesterase (PDE4) on anti-CD3-stimulated interleukin (IL)-4 and IL-5 generation by splenocytes from BALB/c mice infected with Mesocestoides (M) corti. RP 73401 (IC40: 0.011 +/- 0.004 microM) was a very potent inhibitor of anti-CD3-induced IL-4 release, being approximately 40-fold more potent than (+/-)-rolipram (IC40: 0.43 +/- 0.09 microM). A maximal inhibition of 60-70% of the response was achieved at the top concentrations of RP 73401 (1 microM) and rolipram (100 microM). These PDE inhibitors also suppressed IL-5 generation over the same concentration ranges, but the maximal suppression achieved was only 30-40%. R-(-)-rolipram (IC40: 0.39 +/- 0.09 microM) was approximately 6-fold more potent than S-(+)- rolipram (IC40: 2.6 +/- 0.95 microM) in inhibiting IL-4 release. A close correlation (r2 = 0.82) was observed between suppression of IL-4 release by PDE inhibitors and inhibition of CTLL cell PDE4, a form against which R-(-)-rolipram displayed relatively weak inhibitory potency. A poorer correlation (r2 = 0.26) was observed between suppression of IL-4 release and affinities of cAMP PDE inhibitors for the high-affinity rolipram binding site in mouse brain membranes. The cGMP-inhibited PDE (PDE3) inhibitor, siguazodan, had little or no effect (IC40 > 100 microM) on anti-CD3-stimulated release of either IL-4 or IL-5 and did not significantly enhance the inhibitory action of RP 73401 on the release of either of these cytokines. Finally, RP 73401 (IC50: 0.41 +/- 0.19 nM) inhibited anti-CD3-stimulated DNA synthesis in splenocyte preparations from M. corti-infected mice and siguazodan (10 microM) had no effect on this response, either alone or in combination with the PDE4 inhibitor. The results show that PDE4 inhibitors suppress the release of Th2 cytokines from anti-CD3-stimulated murine spenocytes and that this effect is correlated with inhibition of a low-affinity PDE4 form.
我们研究了咯利普兰、RP 73401（匹拉米司特）以及其他结构各异的3',5'-环磷酸腺苷（cAMP）特异性磷酸二酯酶（PDE4）抑制剂，对感染了考氏中殖孔绦虫（M）的BALB/c小鼠脾细胞经抗CD3刺激后白细胞介素（IL）-4和IL-5生成的抑制作用。RP 73401（IC40：0.011±0.004微摩尔）是抗CD3诱导的IL-4释放的非常有效的抑制剂，其效力比（±）-咯利普兰（IC40：0.43±0.09微摩尔）强约40倍。在RP 73401（1微摩尔）和咯利普兰（100微摩尔）的最高浓度下，对反应的最大抑制率达到60 - 70%。这些PDE抑制剂在相同浓度范围内也抑制IL-5的生成，但达到的最大抑制率仅为30 - 40%。R-（-）-咯利普兰（IC40：0.39±0.09微摩尔）在抑制IL-4释放方面比S-（+）-咯利普兰（IC40：2.6±0.95微摩尔）强约6倍。在PDE抑制剂对IL-4释放的抑制与对CTLL细胞PDE4的抑制之间观察到密切相关性（r2 = 0.82），R-（-）-咯利普兰对该形式显示出相对较弱的抑制效力。在IL-4释放的抑制与cAMP PDE抑制剂对小鼠脑膜中高亲和力咯利普兰结合位点的亲和力之间观察到较差的相关性（r2 = 0.26）。环鸟苷酸抑制的磷酸二酯酶（PDE3）抑制剂西呱佐旦，对抗CD3刺激的IL-4或IL-5释放几乎没有影响（IC40>100微摩尔），并且没有显著增强RP 73401对这两种细胞因子释放的抑制作用。最后，RP 73401（IC50：0.41±0.19纳摩尔）抑制了感染考氏中殖孔绦虫的小鼠脾细胞制剂中抗CD3刺激的DNA合成，西呱佐旦（10微摩尔）单独或与PDE4抑制剂联合使用对该反应均无影响。结果表明，PDE4抑制剂抑制抗CD3刺激的小鼠脾细胞中Th2细胞因子的释放，并且这种作用与对低亲和力PDE4形式的抑制相关。
