Haddad John J, Land Stephen C, Tarnow-Mordi William O, Zembala Marek, Kowalczyk Danuta, Lauterbach Ryszard
Neuroscience Research Laboratory, Department of Anesthesia and Perioperative Care, University of California Medical Center, San Francisco, California 94143, USA.
J Pharmacol Exp Ther. 2002 Feb;300(2):559-66. doi: 10.1124/jpet.300.2.559.
In an attempt to elaborate in vitro on a therapeutic strategy that counteracts an inflammatory signal, we previously reported a novel immunopharmacological potential of glutathione, an antioxidant thiol, in regulating inflammatory cytokines. In the present study, we investigated the hypothesis that selective regulation of phosphodiesterases (PDEs), a family of enzymes that controls intracellular cAMP/cGMP degradation, differentially regulates proinflammatory cytokines. Selective PDE1 inhibition (8-methoxymethyl-3-isobutyl-1-methylxanthine) blockaded lipopolysaccharide-endotoxin (LPS)-mediated biosynthesis of interleukin (IL)-6, but this pathway had no inhibitory effect on tumor necrosis factor-alpha (TNF-alpha). Furthermore, inhibition of PDE3 (amrinone) abolished the effect of LPS on IL-6, but attenuated TNF-alpha production. Reversible competitive inhibition of PDE4 (rolipram) exhibited a potent inhibitory effect on IL-6 and a dual, biphasic (excitatory/inhibitory) effect on TNF-alpha secretion. Blockading PDE5 (4-[[3',4'-(methylenedioxy)benzyl] amino]-6-methoxyquinazoline) showed a high potency in reducing IL-6 production, but in a manner similar to the inhibition of PDE4, exhibited a biphasic effect on TNF-alpha biosynthesis. Simultaneous inhibition of PDE5, 6, and 9 (zaprinast), purported to specifically elevate intracellular cGMP, reduced, in a dose-independent manner, IL-6 and TNF-alpha biosynthesis. Finally, nonselective inhibition of PDE by pentoxifylline suppressed LPS-mediated secretion of IL-6 and TNF-alpha. The involvement of specific PDE isoenzymes in differentially regulating LPS-mediated inflammatory cytokine biosynthesis indicates a novel approach to unravel the potential therapeutic targets that these isozymes constitute during the progression of inflammation within the respiratory epithelium.
为了在体外详细阐述一种对抗炎症信号的治疗策略，我们之前报道了谷胱甘肽（一种抗氧化硫醇）在调节炎症细胞因子方面具有新的免疫药理学潜力。在本研究中，我们探讨了一种假说，即磷酸二酯酶（PDEs）家族（一类控制细胞内cAMP/cGMP降解的酶）的选择性调节可差异性地调节促炎细胞因子。选择性抑制PDE1（8 - 甲氧基甲基 - 3 - 异丁基 - 1 - 甲基黄嘌呤）可阻断脂多糖 - 内毒素（LPS）介导的白细胞介素（IL）-6的生物合成，但该途径对肿瘤坏死因子 - α（TNF - α）没有抑制作用。此外，抑制PDE3（氨力农）消除了LPS对IL - 6的作用，但减弱了TNF - α的产生。PDE4的可逆竞争性抑制（咯利普兰）对IL - 6表现出强效抑制作用，对TNF - α分泌表现出双重、双相（兴奋/抑制）作用。阻断PDE5（4 - [[3',4' - （亚甲二氧基）苄基]氨基] - 6 - 甲氧基喹唑啉）在降低IL - 6产生方面显示出高效力，但与抑制PDE4的方式类似，对TNF - α生物合成表现出双相作用。同时抑制PDE5、6和9（扎普司特），据称可特异性升高细胞内cGMP，以剂量非依赖性方式降低IL - 6和TNF - α的生物合成。最后，己酮可可碱对PDE的非选择性抑制抑制了LPS介导的IL - 6和TNF - α的分泌。特定PDE同工酶参与差异性调节LPS介导的炎症细胞因子生物合成，这表明了一种新的方法来揭示这些同工酶在呼吸道上皮炎症进展过程中构成的潜在治疗靶点。
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