Dexamethasone induces a heat-stress response that ameliorates the conformational consequences on antithrombin of l-asparaginase treatment
Dexamethasone induces a heat-stress response that ameliorates the conformational consequences on antithrombin of l-asparaginase treatment
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DOI：
10.1111/j.1538-7836.2009.03449.x
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发表时间：
2009-07-01
影响因子：
10.4
通讯作者：
Corral, J.
中科院分区：
文献类型：
--
作者：
Hernandez-Espinosa, D.;Minano, A.;Corral, J.
背景：l-天冬酰胺酶（l-ASP）治疗急性淋巴细胞白血病患者会导致严重的抗凝血酶缺乏，这是由于肝细胞内质网（ER）内的丝氨酸酶在细胞内的保留，以及随后的血栓形成风险。有趣的是，地塞米松与l-ASP联合用药似乎可以降低血栓形成的风险。目的：我们研究了地塞米松和强的松两种皮质激素对l-ASP治疗抗凝血酶构象的影响。患者/方法：在患者、细胞和小鼠模型中研究抗凝血酶的水平、活性、构象和免疫组织学特征。由于类固醇受体-热应激反应（HSR）轴的重要性，以及未折叠蛋白反应（UPR）在构象疾病中的作用，我们还评估了Hsp27、Hsp70、Hsp90、HSF-1和ER伴侣（Grp78和Grp94）。结果：在所有模型中，l-ASP单独或与强的松联合引起细胞内抗凝血酶潴留并伴有严重缺乏。相反，l-ASP与地塞米松联合使用可以改善丝氨酸蛋白的缺乏和细胞内保留，这与热休克蛋白和er伴侣蛋白的表达增加有关。结论：这些结果表明，地塞米松对l-ASP对抗凝血酶的构象后果具有保护作用，这是HSR和UPR加剧的结果，有助于解释采用这种治疗方案的患者血栓形成风险降低的原因。
Background: l-asparaginase (l-ASP) treatment of patients with acute lymphoblastic leukemia causes a severe antithrombin deficiency by intracellular retention of this serpin within the endoplasmic reticulum (ER) of hepatic cells, and a subsequent risk of thrombosis. Interestingly, co-administration of dexamethasone with l-ASP seems to reduce the risk of thrombosis. Objectives: We have investigated the effect of two corticoids, dexamethasone and prednisone, on the conformational consequences of l-ASP treatment on antithrombin. Patients/methods: Levels, activity, conformation and immunohistological features of antithrombin were studied in patients, cell and mice models. Because of the importance of the steroid receptor-heat stress response (HSR) axis, and the role of unfolded protein response (UPR) in conformational diseases, we also evaluated Hsp27, Hsp70, Hsp90, HSF-1 and ER chaperons (Grp78 and Grp94). Results: In all models, l-ASP alone or in combination with prednisone caused the intracellular retention of antithrombin associated with a severe deficiency. In contrast, the combination of l-ASP with dexamethasone ameliorated both the deficiency and intracellular retention of the serpin, which is associated with increased expression of heat shock proteins and ER-chaperons. Conclusions: These results suggest a protective effect of dexamethasone on the conformational consequences of l-ASP on antithrombin as a result of exacerbated HSR and UPR that help to explain the reduced risk of thrombosis reported in patients that follow this scheme of treatment.