Increased expression of endoplasmic reticulum stress and unfolded protein response genes in peripheral blood mononuclear cells from patients with limited cutaneous systemic sclerosis and pulmonary arterial hypertension.
Increased expression of endoplasmic reticulum stress and unfolded protein response genes in peripheral blood mononuclear cells from patients with limited cutaneous systemic sclerosis and pulmonary arterial hypertension.
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DOI：
10.1002/art.37891
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发表时间：
2013-05
影响因子：
--
通讯作者：
Trojanowska, Maria
中科院分区：
文献类型：
--
作者：
Lenna, Stefania;Farina, Alessandra G.;Martyanov, Viktor;Christmann, Romy B.;Wood, Tammara A.;Farber, Harrison W.;Scorza, Raffaella;Whitfield, Michael L.;Lafyatis, Robert;Trojanowska, Maria
肺动脉高压（PAH）是局限性皮肤系统性硬化症（lcSSc）的常见并发症，与外周血单个核细胞（PBMCs）炎症和血管损伤标志物的改变有关。内质网（ER）应激和未折叠蛋白反应（UPR）与自身免疫性和炎症性疾病有关。本研究的目的是评估内质网应激/UPR标志物是否存在于lcSSc-PAH患者的pbmc中。从健康对照（HC, n=36）和患有和不患有PAH的lcSSc患者（lcsc -PAH, n=32; lcsc - nopah, n=34）中纯化pbmc。应用DNA芯片技术分析了TG刺激下HC PBMCs的基因表达。用qPCR对HC和lcSSc PBMCs进行基因验证。几种内质网应激/UPR基因，包括免疫球蛋白重链结合蛋白（BiP）、激活转录因子-4和-6 （ATF4和ATF6）以及X-box结合蛋白的剪接形式（XBP1）在lcSSc pbmc中上调，其中PAH患者的水平最高。TG上调热休克蛋白（HSP）和干扰素调节基因在控制PBMCs。在lcSSc患者的pbmc中也发现了选定的HSP基因，特别是DNAJB1和ifn相关基因的水平显著升高，而IRF4的水平显著降低。在lcSSc PBMCs中，DNAJB1与PAH疾病严重程度（PAP）呈正相关（r = 0.56, p<0.05），内质网应激标志物与IL-6水平呈正相关（r = 0.53, p< 0.0001）。本研究证实了选择的内质网应激/UPR标记与lcSSc- pah之间的关联，提示内质网应激/UPR可能有助于lcSSc循环免疫细胞功能的改变。
Pulmonary arterial hypertension (PAH), a common complication of limited cutaneous systemic sclerosis (lcSSc), is associated with alterations of markers of inflammation and vascular damage in peripheral blood mononuclear cells (PBMCs). Endoplasmic reticulum (ER) stress and unfolded protein response (UPR) have been implicated in autoimmune and inflammatory diseases. The goal of this study was to assess whether markers of ER stress/UPR are present in PBMCs from lcSSc-PAH patients. PBMCs were purified from healthy controls (HC, n=36) and lcSSc patients, with and without PAH (lcSSc-PAH, n=32; lcSSc-NoPAH, n=34). Gene expression in HC PBMCs stimulated with thapsigargin (TG) was analyzed by DNA microarray. Genes were validated by qPCR in HC and lcSSc PBMCs. Several ER stress/UPR genes, including Immunoglobulin-heavy-chain binding protein (BiP), Activating Transcription Factor-4 and -6 (ATF4 and ATF6) and a spliced form of X-box binding protein (XBP1) were upregulated in lcSSc PBMCs, with the highest levels in patients with PAH. TG upregulated Heat shock proteins (HSP) and Interferon-regulated genes in control PBMCs. Selected HSP genes, particularly DNAJB1, and IFN-related genes were also found at significantly elevated levels in PBMCs from lcSSc patients, while IRF4 was significantly decreased. There was a positive correlation between DNAJB1 and severity of PAH disease (PAP) (r = 0.56, p<0.05) and between ER stress markers and IL-6 levels (r = 0.53, p< 0.0001) in lcSSc PBMCs. This study demonstrates association between select ER stress/UPR markers and lcSSc-PAH suggesting that ER stress/UPR may contribute to the altered function of circulating immune cells in lcSSc.
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影响因子：
4.9
作者：
Gourh P;Arnett FC;Assassi S;Tan FK;Huang M;Diekman L;Mayes MD;Reveille JD;Agarwal SK
通讯作者：
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影响因子：
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作者：
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24
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硬皮病皮肤的基因表达特征中的分子亚群。
影响因子：
3.7
作者：
Milano A;Pendergrass SA;Sargent JL;George LK;McCalmont TH;Connolly MK;Whitfield ML
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Whitfield ML
影响因子：
8.7
作者：
Biswas PS;Bhagat G;Pernis AB
通讯作者：
Pernis AB