IL-1β converting enzyme is a target for nitric oxide-releasing aspirin:: New insights in the antiinflammatory mechanism of nitric oxide-releasing nonsteroidal antiinflammatory drugs
IL-1β converting enzyme is a target for nitric oxide-releasing aspirin:: New insights in the antiinflammatory mechanism of nitric oxide-releasing nonsteroidal antiinflammatory drugs
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DOI：
10.4049/jimmunol.165.9.5245
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发表时间：
2000-11-01
影响因子：
4.4
通讯作者：
Morelli, A
中科院分区：
文献类型：
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作者：
Fiorucci, S;Santucci, L;Morelli, A
Caspase-1，IL-1 β转化酶（ICE），是IL-1 β和IL-18细胞内加工/成熟所必需的，NO释放非甾体类抗炎药（NSAID）是一类新的NSAID衍生物，可保护胃粘膜。在此，我们测试了NCX-4016，一种NO-阿司匹林衍生物，抑制内毒素（LPS）攻击的单核细胞释放促炎细胞因子的假设，我们的结果表明，将LPS刺激的人单核细胞暴露于NCX-4016导致IL-1 β、IL-8、IL-12、IL-18、IFN-γ和TNF-α释放的40-80%抑制，其中IL-1 β和IL-18的EC 50为10-20 μ M，用NCX-4016孵育LPS引发的单核细胞导致细胞内NO形成，如通过测量亚硝酸盐/硝酸盐、细胞内cGMP浓度和细胞内NO形成所评估的。将LPS刺激的单核细胞暴露于阿司匹林或塞来昔布导致前列腺素E-2生成的90%抑制，但对细胞因子释放没有影响。与NO供体S-亚硝基-N-乙酰基-D-L-青霉胺类似，NCX-4016抑制半胱天冬酶-1活性，EC 50约为20 μ M。通过添加DTT，NCX-4016对caspase-1的抑制是可逆的，这与作为caspase-1抑制机制的S-亚硝基化一致。如通过评估ICE p20亚基的释放所测量的，NCX-4016而不是阿司匹林阻止ICE活化。IL-18免疫中和导致从LPS刺激的单核细胞释放的IL-1 β、IL-8、IFN-γ和TNF-α减少60-80%。这些数据表明，用NCX-4016孵育人单核细胞引起细胞内NO形成，并通过抑制半胱天冬酶-1活性抑制IL-1 β和IL-18加工。Caspase-1抑制是NO-阿司匹林的一种新的、不依赖于环氧合酶的促凋亡机制。
Caspase-1, the IL-1 beta converting enzyme (ICE), is required for intracellular processing/maturation of IL-1 beta and IL-18, NO releasing nonsteroidal antiinflammatory drugs (NSAIDs) are a new class of NSAID derivatives that spare the gastric mucosa, Here, we tested the hypothesis that NCX-4016, a NO-aspirin derivative, inhibits proinflammatory cytokine release from endotoxin (LPS)-challenged monocytes, Our results demonstrated that exposing LPS-stimulated human monocytes to NCX-4016 resulted in a 40-80% inhibition of IL-1 beta, IL-8, IL-12, IL-18, IFN-gamma, and TNF-alpha release with an EC50 of 10-20 muM for IL-1 beta and IL-18, Incubating LPS-primed monocytes with NCX-4016 resulted in intracellular NO formation as assessed by measuring nitrite/nitrate, intracellular cGMP concentration, and intracellular NO formation. Exposing LPS-stimulated monocytes to aspirin or celecoxib caused a 90% inhibition of prostaglandin E-2 generation but had no effect on cytokine release. NCX-4016, similar to the NO donor S-nitroso-N-acetyl-D-L-penicillamine, inhibited caspase-1 activity with an EC50 of approximate to 20 muM. The inhibition of caspase-1 by NCX-4016 was reversible by the addition of DTT, which is consistent with S-nitrosylation as the mechanism of caspase-1 inhibition. NCX-4016, but not aspirin, prevented ICE activation as measured by assessing the release of ICE p20 subunit, IL-18 immunoneutralization resulted in a 60-80% reduction of IL-1 beta, IL-8, IFN-gamma, and TNF-alpha release from LPS-stimulated monocytes, Taken together, these data indicate that incubating human monocytes with NCX-4016 causes intracellular NO formation and suppresses IL-1 beta and IL-18 processing by inhibiting caspase-1 activity. Caspase-1 inhibition is a new, cycloxygenase-independent antiinflammatory mechanism of NO-aspirin.