α1-Antitrypsin, old dog, new tricks -: α1-Antitrypsin exerts in vitro anti-inflammatory activity in human monocytes by elevatin cAMP
α1-Antitrypsin, old dog, new tricks -: α1-Antitrypsin exerts in vitro anti-inflammatory activity in human monocytes by elevatin cAMP
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DOI：
10.1074/jbc.m607976200
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发表时间：
2007-03-23
影响因子：
4.8
通讯作者：
Stevens, Tim
中科院分区：
文献类型：
--
作者：
Janciauskiene, Sabina M.;Nita, Izabela M.;Stevens, Tim
丝氨酸蛋白酶活性的调节被认为是α(1)-抗胰蛋白酶(AAT)功能的唯一机制。然而，最近关于 AAT 抗炎作用的报道很难与这种经典机制相一致。我们发现，AAT 在体外的两个关键活性，即抑制内毒素刺激的肿瘤坏死因子-a 和增强人单核细胞中的白介素-10，是通过 cAMP 的升高和 cAMP 依赖性蛋白激酶 A 的激活介导的。正如这种机制所预期的那样，AAT 介导 cAMP 的升高以及对内毒素刺激的肿瘤坏死因子-a 和白细胞介素 10 的影响。 当磷酸二酯酶抑制剂咯利普兰阻断 cAMP 的分解代谢时，白细胞介素 10 会增强。在缺乏蛋白酶抑制剂活性的 AAT 修饰形式中仍然可以观察到这些效应。
Regulation of serine protease activity is considered to be the sole mechanism for the function of alpha(1)-antitrypsin (AAT). However, recent reports of the anti-inflammatory effects of AAT are hard to reconcile with this classical mechanism. We discovered that two key activities of AAT in vitro, namely inhibition of endotoxin-stimulated tumor necrosis factor-a and enhancement of interleukin-10 in human monocytes, are mediated by an elevation of cAMP and activation of cAMP-dependent protein kinase A. As expected with this type of mechanism, the AAT mediated rise in cAMP and the impact on endotoxin-stimulated tumor necrosis factor-a and interleukin-10 was enhanced when the catabolism of cAMP was blocked by the phosphodiesterase inhibitor rolipram. These effects were still observed with modified forms of AAT lacking protease inhibitor activity.