Miskolci Veronika, Ghosh Chandra C, Rollins Janet, Romero Carlos, Vu Hai-Yen, Robinson Staci, Davidson Dennis, Vancurova Ivana
Department of Biology, St. John's University, NY 11439, USA.
Biochem Biophys Res Commun. 2006 Dec 15;351(2):354-60. doi: 10.1016/j.bbrc.2006.10.045. Epub 2006 Oct 16.
Tumor necrosis factor-alpha (TNFalpha) is a potent pro-inflammatory cytokine that plays a major role in the pathogenesis of acute and chronic inflammatory disorders such as septic shock and arthritis, respectively. Leukocytes stimulated with inflammatory signals such as lipopolysaccharide (LPS) are the predominant producers of TNFalpha, and thus control of TNFalpha release from stimulated leukocytes represents a potential therapeutic target. Here, we report that leptomycin B (LMB), a specific inhibitor of CRM1-dependent nuclear protein export, inhibits TNFalpha release from LPS-stimulated human peripheral blood neutrophils and mononuclear cells. In addition, immunofluorescence confocal microscopy and immunoblotting analysis indicate that TNFalpha is localized in the nucleus of human neutrophils and mononuclear cells. This study demonstrates that the cellular release of TNFalpha from stimulated leukocytes is mediated by the CRM1-dependent nuclear export mechanism. Inhibition of CRM1-dependent cellular release of TNFalpha could thus provide a novel therapeutic approach for disorders involving excessive TNFalpha release.
肿瘤坏死因子-α（TNFα）是一种强效促炎细胞因子，分别在诸如脓毒性休克和关节炎等急慢性炎症性疾病的发病机制中起主要作用。受到诸如脂多糖（LPS）等炎症信号刺激的白细胞是TNFα的主要产生者，因此控制受刺激白细胞释放TNFα代表了一个潜在的治疗靶点。在此，我们报告，作为CRM1依赖性核蛋白输出的特异性抑制剂，雷帕霉素B（LMB）可抑制LPS刺激的人外周血中性粒细胞和单核细胞释放TNFα。此外，免疫荧光共聚焦显微镜和免疫印迹分析表明，TNFα定位于人中性粒细胞和单核细胞的细胞核中。本研究证明，受刺激白细胞释放TNFα的细胞过程是由CRM1依赖性核输出机制介导的。因此，抑制CRM1依赖性的TNFα细胞释放可为涉及TNFα过度释放的疾病提供一种新的治疗方法。
