Critical role for CCAAT/enhancer-binding protein β in immune complex-induced acute lung injury.
Critical role for CCAAT/enhancer-binding protein β in immune complex-induced acute lung injury.
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DOI：
10.4049/jimmunol.1200877
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发表时间：
2012-08-01
期刊：
影响因子：
--
通讯作者：
Gao H
中科院分区：
文献类型：
--
作者：
Yan C;Wu M;Cao J;Tang H;Zhu M;Johnson PF;Gao H
CCAAT/增强子结合蛋白（C/ ebp），特别是C/EBPβ和C/EBPδ，已知参与许多与炎症相关的基因的调节。然而，关于C/EBPβ和C/EBPδ在急性肺炎症和损伤中的激活和功能知之甚少。本研究表明，在肺内IgG免疫复合物沉积后，C/EBPβ和C/EBPδ活化在肺和肺泡巨噬细胞中被触发。我们进一步发现，与野生型小鼠相比，携带C/EBPβ基因靶向缺失的小鼠在支气管肺泡灌洗液（BAL）中的通透性指数（肺血管白蛋白泄漏）、肺中性粒细胞积累（MPO活性）、白细胞总数和中性粒细胞的显著降低。此外，与野生型小鼠相比，突变小鼠在BAL液中表达的TNF-α、IL-6、CXC/CC趋化因子和sICAM-1蛋白以及在IgG免疫复合物损伤的肺中表达的相应mrna明显减少。这些表型与形态学肺损伤的显著减少有关。相比之下，C/EBPδ缺乏对IgG免疫复合物诱导的肺损伤无影响。与野生型细胞相比，IgG免疫复合物刺激的C/ ebp β缺陷肺泡巨噬细胞释放的TNF-α、IL-6、巨噬细胞炎症蛋白(MIP)-2、角质形成细胞来源的趋化因子（KC）和MIP-1α显著减少。在小鼠肺泡巨噬细胞系中，在siRNA消融C/EBPβ后，观察到IgG免疫复合物诱导的炎症介质产生类似的减少。这些发现暗示C/EBPβ是IgG免疫复合物诱导的炎症反应和肺损伤的关键调节因子。
The CCAAT/enhancer-binding proteins (C/EBPs), particularly C/EBPβ and C/EBPδ, are known to participate in the regulation of many genes associated with inflammation. However, very little is known regarding the activation and functions of C/EBPβ and C/EBPδ in acute lung inflammation and injury. Here we show that both C/EBPβ and C/EBPδ activation are triggered in lungs and in alveolar macrophages following intrapulmonary deposition of IgG immune complexes. We further show that mice carrying a targeted deletion of the C/EBPβ gene displayed significant attenuation of the permeability index (lung vascular leak of albumin), lung neutrophil accumulation (MPO activity), total number of white blood cells, and neutrophils in bronchial alveolar lavage (BAL) fluids compared to wild-type mice. Moreover, the mutant mice expressed considerably less TNF-α, IL-6, and CXC/CC chemokine and sICAM-1 proteins in BAL fluids, and corresponding mRNAs in the IgG immune complex-injured lung, compared to wild-type mice. These phenotypes were associated with a significant reduction in morphological lung injury. In contrast, C/EBPδ deficiency had no effect on IgG immune complex-induced lung injury. IgG immune complex-stimulated C/EBPβ-deficient alveolar macrophages released significantly less TNF-α, IL-6, macrophage inflammatory protein (MIP)-2, keratinocyte cell-derived chemokine (KC), and MIP-1α compared to wild-type cells. Similar decreases in IgG immune complex-induced inflammatory mediator production were observed following siRNA ablation of C/EBPβ in a murine alveolar macrophage cell line. These findings implicate C/EBPβ as a critical regulator of IgG immune complex-induced inflammatory responses and injury in the lung.
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DOI：
10.4049/jimmunol.0802971
发表时间：
2009-06-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Lu YC;Kim I;Lye E;Shen F;Suzuki N;Suzuki S;Gerondakis S;Akira S;Gaffen SL;Yeh WC;Ohashi PS
通讯作者：
Ohashi PS
影响因子：
5.3
作者：
Cantwell, CA;Sterneck, E;Johnson, PF
通讯作者：
Johnson, PF
影响因子：
4.4
作者：
Gao, Hongwei;Hoesel, L. Marco;Ward, Peter A.
通讯作者：
Ward, Peter A.
影响因子：
5.5
作者：
Serio, KJ;Reddy, KV;Bigby, TD
通讯作者：
Bigby, TD
影响因子：
4.8
作者：
Caivano, M;Gorgoni, B;Poli, V
通讯作者：
Poli, V