Suppression of GATA-3 nuclear import and phosphorylation: a novel mechanism of corticosteroid action in allergic disease.
Suppression of GATA-3 nuclear import and phosphorylation: a novel mechanism of corticosteroid action in allergic disease.
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DOI：
10.1371/journal.pmed.1000076
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发表时间：
2009-05-12
期刊：
影响因子：
15.8
通讯作者：
Barnes PJ
中科院分区：
文献类型：
--
作者：
Maneechotesuwan K;Yao X;Ito K;Jazrawi E;Usmani OS;Adcock IM;Barnes PJ
Peter Barnes及其同事发现，皮质类固醇通过两种相互作用机制抑制Th2细胞因子的表达，从而对GATA-3产生强有力的抑制作用。这种皮质类固醇作用的新机制可能有助于解释皮质类固醇在过敏性疾病中的疗效。GATA-3在T helper-2 （Th2）细胞中调节白细胞介素(IL)-4、IL-5和IL-13的表达中起关键作用，因此是过敏性疾病的关键介质。皮质类固醇在抑制过敏性炎症方面非常有效，但其对GATA-3的影响尚不清楚。我们在体内外研究了皮质类固醇丙酸氟替卡松对人t淋巴细胞GATA-3调控的影响。在T淋巴细胞系（HuT-78）和体外抗cd3和抗cd28刺激的外周血单核细胞中，我们证明了氟替卡松通过一种独立于核因子-κB的机制抑制GATA-3的核易位和Th2细胞因子的表达，部分原因是GATA-3和配体激活的糖皮质激素受体通过核进口蛋白-α进行核运输的竞争。此外，氟替卡松诱导丝裂原活化蛋白激酶（MAPK）磷酸酶-1 （mmp -1）的表达，mmp -1是p38 MAPK的内源性抑制剂，是GATA-3核易位所必需的。氟替卡松的这些抑制作用是快速、有效和持久的。我们还在体内证明了吸入氟替卡松抑制哮喘患者外周血淋巴细胞中GATA-3核易位。皮质类固醇通过两种相互作用机制有效抑制Th2细胞因子的表达，从而对GATA-3具有有效的抑制作用。这种新的作用机制可能是糖皮质激素治疗过敏性疾病的显著临床疗效的原因。免疫系统保护人体免受病毒、细菌、寄生虫和真菌的侵害。当这些外来入侵者进入人体时，被称为T淋巴细胞的免疫系统细胞识别入侵者表面的特定分子，并释放化学信使（细胞因子），招募并激活其他类型的免疫细胞，然后攻击入侵者。然而，有时免疫系统对通常无害的物质（例如，屋尘螨或草花粉；科学家称这些物质为过敏原）产生反应，引发过敏性疾病，如哮喘或花粉热。接触过敏原会激活一种叫做T辅助细胞-2 （Th2）的T淋巴细胞，这种细胞随后会产生（表达）三种细胞因子，分别是白细胞介素-4 （IL-4）、IL-5和IL-13。这些细胞因子最终会导致身体接触过敏原的部分出现炎症（肿胀）。皮质类固醇可抑制Th2细胞表达细胞因子，常用于治疗过敏性疾病中的炎症。针对这些常见疾病的其他治疗方法——美国约有5000万人患有过敏性疾病——包括通过使用各种免疫疗法，尽量减少与过敏原的接触，减少免疫系统对过敏原的反应。科学家们知道，皮质类固醇通过与免疫系统细胞中称为糖皮质激素受体的蛋白质结合来减轻过敏性炎症。在与皮质类固醇结合后，这些受体进入细胞核（细胞中包含其基因的部分），在那里它们抑制某些促炎基因的表达。然而，皮质类固醇如何抑制Th2细胞因子的表达尚不清楚。这些细胞因子表达和过敏性炎症的关键调节因子是一种叫做GATA-3的转录因子。转录因子是一种通过与编码其他蛋白质的基因中的特定序列结合来控制其他蛋白质表达的蛋白质。在这项研究中，研究人员试图通过研究皮质类固醇氟替卡松对T淋巴细胞中GATA-3活性的调节作用来发现更多关于皮质类固醇如何减轻过敏性炎症的信息。转录因子必须进入细胞核（所谓的核易位）来控制其靶基因的表达，因此研究人员首先询问氟替卡松是否影响GATA-3的细胞定位。他们报告说，氟替卡松治疗在培养皿中生长的活化T淋巴细胞，抑制了GATA-3的核易位，降低了Th2细胞因子的表达。其他实验表明，抑制GATA-3核易位的部分原因是与氟替卡松结合的糖皮质激素受体与GATA-3之间竞争与核输入所需的蛋白质-α的结合。然而，氟替卡松还以第二种方式阻止GATA-3的核易位。在GATA-3与输入α结合之前，必须在GATA-3的特定位点添加磷酸基团。这种“磷酸化”需要一种叫做p38 MAP激酶的酶，研究人员发现，氟替卡松治疗活化的T淋巴细胞诱导了MAP激酶磷酸酶-1的表达，这是一种p38 MAP激酶抑制剂。最后，当研究人员用吸入氟替卡松治疗7例轻度哮喘患者时，他们发现氟替卡松还能抑制患者血液中循环淋巴细胞中的GATA-3核易位。这些在实验室和患者身上获得的发现表明，皮质类固醇通过两种相互作用的机制抑制Th2细胞因子的表达，从而减轻过敏性炎症。他们认为，皮质类固醇通过与GATA-3竞争与输入蛋白α结合，并通过阻止GATA-3的磷酸化（一种允许GATA-3与输入蛋白α结合的修饰），阻止Th2细胞因子表达的关键调节因子GATA-3的核易位。皮质类固醇作用的这种双重机制可能有助于解释为什么这些药物在治疗过敏性疾病方面如此有效，尽管还需要进一步的实验来证明，居住在过敏性炎症部位的淋巴细胞对皮质类固醇的反应与血液中的淋巴细胞相同。最后，这些发现表明磷酸化GATA-3与输入蛋白α之间的相互作用可能是过敏性疾病新治疗的潜在靶点。请通过本摘要的在线版本http://dx.doi.org/10.1371/journal.pmed.1000076访问这些网站。美国国家过敏和传染病研究所提供有关过敏性疾病的信息和免疫系统的简单描述英国国家健康服务选择服务提供有关过敏的信息从MedlinePlus（英语和西班牙语）可获得有关过敏的其他信息的链接
Peter Barnes and colleagues show that corticosteroids have a potent inhibitory effect on GATA-3 via two interacting mechanisms that suppress Th2 cytokine expression. This novel mechanism of corticosteroid action may help explain the efficacy of corticosteroids in allergic diseases. GATA-3 plays a critical role in regulating the expression of the cytokines interleukin (IL)-4, IL-5, and IL-13 from T helper-2 (Th2) cells and therefore is a key mediator of allergic diseases. Corticosteroids are highly effective in suppressing allergic inflammation, but their effects on GATA-3 are unknown. We investigated the effect of the corticosteroid fluticasone propionate on GATA-3 regulation in human T-lymphocytes in vitro and in vivo. In a T lymphocyte cell line (HuT-78) and peripheral blood mononuclear cells stimulated by anti-CD3 and anti-CD28 in vitro we demonstrated that fluticasone inhibits nuclear translocation of GATA-3 and expression of Th2 cytokines via a mechanism independent of nuclear factor-κB and is due, in part, to competition between GATA-3 and the ligand-activated glucocorticoid receptor for nuclear transport through the nuclear importer importin-α. In addition, fluticasone induces the expression of mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1), the endogenous inhibitor of p38 MAPK, which is necessary for GATA-3 nuclear translocation. These inhibitory effects of fluticasone are rapid, potent, and prolonged. We also demonstrated that inhaled fluticasone inhibits GATA-3 nuclear translocation in peripheral blood lymphocytes of patients with asthma in vivo. Corticosteroids have a potent inhibitory effect on GATA-3 via two interacting mechanisms that potently suppress Th2 cytokine expression. This novel mechanism of action of corticosteroids may account for the striking clinical efficacy of corticosteroids in the treatment of allergic diseases. Please see later in the article for Editors' Summary The immune system protects the human body from viruses, bacteria, parasites, and fungi. When one of these foreign invaders enters the body, immune system cells called T lymphocytes recognize specific molecules on the invader's surface and release chemical messengers (cytokines) that recruit and activate other types of immune cell, which then attack the invader. Sometimes, however, the immune system responds to a normally harmless material (for example, house-dust mites or grass pollen; scientists call these materials allergens) and triggers an allergic disease such as asthma or hay fever. Contact with an allergen activates a type of T lymphocyte called a T helper-2 (Th2) cell that subsequently makes (expresses) three cytokines called interleukin-4 (IL-4), IL-5, and IL-13. These cytokines ultimately cause inflammation (swelling) of the part of the body exposed to the allergen. Corticosteroids, which suppress the expression of cytokines by Th2 cells, are often used to treat inflammation in allergic diseases. Other treatments for these common conditions—about 50 million people in the US have an allergic disease—include minimizing exposure to allergens and diminishing the response of the immune system to allergens by using various immunotherapies. Scientists know that corticosteroids reduce allergic inflammation by binding to proteins in immune system cells called glucocorticoid receptors. After binding to a corticosteroid, these receptors move into the nucleus of the cell (the part of the cell that contains its genes), where they suppress the expression of certain proinflammatory genes. However, it is still not known how corticosteroids inhibit the expression of Th2 cytokines. A key regulator of the expression of these cytokines and of allergic inflammation is a transcription factor called GATA-3. Transcription factors are proteins that control the expression of other proteins by binding to specific sequences in the genes that encode them. In this study, the researchers try to discover more about how corticosteroids reduce allergic inflammation by investigating the effects of the corticosteroid fluticasone on the regulation of GATA-3 activity in T lymphocytes. Transcription factors have to move into the nucleus of cells (so-called nuclear translocation) to control the expression of their target genes, so the researchers first asked whether fluticasone affects the cellular localization of GATA-3. Fluticasone treatment of activated T lymphocytes growing in dishes, they report, inhibited the nuclear translocation of GATA-3 and reduced Th2 cytokine expression. Other experiments showed that the inhibition of GATA-3 nuclear translocation was partly caused by competition between the glucocorticoid receptor bound to fluticasone and GATA-3 for binding to importin-α, a protein that is required for nuclear import. However, fluticasone also prevented the nuclear translocation of GATA-3 in a second way. Before GATA-3 can bind to importin-α, phosphate groups have to be added to specific sites in GATA-3. This “phosphorylation” requires an enzyme called p38 MAP kinase, and the researchers found that fluticasone treatment of activated T lymphocytes induced the expression of MAP kinase phophatase-1, a p38 MAP kinase inhibitor. Finally, when the researchers treated seven patients with mild asthma with inhaled fluticasone, they found that fluticasone also inhibited GATA-3 nuclear translocation in the lymphocytes circulating in the patients' blood. These findings, obtained both in the laboratory and in patients, suggest that corticosteroids inhibit the expression of Th2 cytokines and thus reduce allergic inflammation through two interacting mechanisms. They suggest that corticosteroids prevent the nuclear translocation of GATA-3, a key regulator of Th2 cytokine expression, by competing with GATA-3 for binding to importin-α and by preventing the phosphorylation of GATA-3, a modification that allows GATA-3 to bind to importin-α. This dual mechanism of corticosteroid action may help to explain why these drugs are so effective in the treatment of allergic diseases, although further experiments are needed to show that the lymphocytes resident at sites of allergic inflammation respond to corticosteroids in the same way as lymphocytes in the blood. Finally, these findings suggest that the interaction between phosphorylated GATA-3 and importin-α might be a potential target for new treatments for allergic diseases. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000076. The US National Institute of Allergy and Infectious Diseases provides information on allergic diseases and a simple description of the immune system The UK National Health Service Choices service provides information about allergies Links to other information about allergies are available from MedlinePlus (in English and Spanish)
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通过反义诱导的GATA-3表达的局部阻断来治疗过敏性气道炎症和反应性过高。
影响因子：
15.3
作者：
Finotto, S;De Sanctis, G T;Lehr, H A;Herz, U;Buerke, M;Schipp, M;Bartsch, B;Atreya, R;Schmitt, E;Galle, P R;Renz, H;Neurath, M F
通讯作者：
Neurath, M F
DOI：
10.1016/j.bbamcr.2004.03.003
发表时间：
2004-05-03
影响因子：
5.1
作者：
Kumar, S;Chaturvedi, NK;Tyagi, RK
通讯作者：
Tyagi, RK
影响因子：
11.4
作者：
PICARD, D;YAMAMOTO, KR
通讯作者：
YAMAMOTO, KR
影响因子：
15.9
作者：
Ray, A;Cohn, L
通讯作者：
Cohn, L
影响因子：
8.2
作者：
Heitzer, Marjet D.;Wolf, Irene M.;DeFranco, Donald B.
通讯作者：
DeFranco, Donald B.