Ablation of Glutaredoxin-1 Attenuates Lipopolysaccharide-Induced Lung Inflammation and Alveolar Macrophage Activation
Ablation of Glutaredoxin-1 Attenuates Lipopolysaccharide-Induced Lung Inflammation and Alveolar Macrophage Activation
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DOI：
10.1165/rcmb.2009-0136oc
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发表时间：
2011-04-01
影响因子：
6.4
通讯作者：
Janssen-Heininger, Yvonne M. W.
中科院分区：
文献类型：
--
作者：
Aesif, Scott W.;Anathy, Vikas;Janssen-Heininger, Yvonne M. W.
蛋白S-谷胱甘肽化（PSSG），一个可逆的反应性半胱氨酸的翻译后修饰，最近出现的调节机制，影响不同的细胞信号级联。细胞PSSG的程度由氧化还原酶谷氧还蛋白-1（Grx 1）控制，这是一种特异性脱谷胱甘肽蛋白质的胞质酶。在这里，我们试图评估Grx 1基因消融对PSSG和LPS诱导的肺部炎症的影响。与PBS对照小鼠相比，WT（WT）小鼠肺组织和支气管肺泡灌洗液（BAL）中的Grx 1活性在对LPS的反应中增加。Glrx 1（-/-）小鼠始终显示BAL回收的炎性细胞总数轻微但无统计学意义的减少。然而，与WT小鼠相比，Glrx 1（-/-）小鼠中BAL中LPS诱导的IL-1 β、TNF-α、IL-6和粒细胞/单核细胞集落刺激因子（GM-CSF）浓度显著降低。PSSG反应性的原位评估和PSSG含量的生物化学评估表明，与WT小鼠或PBS对照小鼠相比，Glrx 1（-/-）动物对LPS的反应性肺组织增加。我们还证明，PSSG反应是突出的肺泡巨噬细胞（AM）。WT和Glrx 12/2小鼠的比较BAL分析显示，与WT细胞相比，Glrx 12/2小鼠中AM更少且更小，显示出NF-κ B B家族成员的表达显著降低，RelA的核转位受损，NF-κ B依赖性细胞因子水平较低。综上所述，这些结果表明，Grx 1通过控制S-谷胱甘肽敏感的信号通路如NF-κ B来调节炎症介质的产生，并且Grx 1表达对AM的激活至关重要。
Protein S-glutathionylation (PSSG), a reversible posttranslational modification of reactive cysteines, recently emerged as a regulatory mechanism that affects diverse cell-signaling cascades. The extent of cellular PSSG is controlled by the oxidoreductase glutaredoxin-1 (Grx1), a cytosolic enzyme that specifically de-glutathionylates proteins. Here, we sought to evaluate the impact of the genetic ablation of Grx1 on PSSG and on LPS-induced lung inflammation. In response to LPS, Grx1 activity increased in lung tissue and bronchoalveolar lavage (BAL) fluid in WT(WT) mice compared with PBS control mice. Glrx1(-/-) mice consistently showed slight but statistically insignificant decreases in total numbers of inflammatory cells recovered by BAL. However, LPS-induced concentrations of IL-1 beta, TNF-alpha, IL-6, and Granulocyte/Monocyte Colony-Stimulating Factor (GM-CSF) in BAL were significantly decreased in Glrx1(-/-) mice compared with WT mice. An in situ assessment of PSSG reactivity and a biochemical evaluation of PSSG content demonstrated increases in the lung tissue of Glrx1(-/-) animals inresponse to LPS, compared with WT mice or PBS control mice. We also demonstrated that PSSG reactivity was prominent in alveolar macrophages (AMs). Comparative BAL analyses from WT and Glrx12/2 mice revealed fewer and smaller AMs in Glrx12/2 mice, which showed a significantly decreased expression of NF-kappa B family members, impaired nuclear translocation of RelA, and lower levels of NF-kappa B-dependent cytokines after exposure toLPS, compared with WT cells. Taken together, these results indicate that Grx1 regulates the production of inflammatory mediators through control of S-glutathionylation-sensitive signaling pathways such as NF-kappa B, and that Grx1 expression is critical to the activation of AMs.