Janex-1是JAK3抑制剂，可改善肿瘤坏死因子-α诱导的细胞粘附分子表达，并改善内毒素血症小鼠的心肌血管通透性。,International Journal of Molecular Medicine

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Janex-1是JAK3抑制剂，可改善肿瘤坏死因子-α诱导的细胞粘附分子表达，并改善内毒素血症小鼠的心肌血管通透性。
International Journal of Molecular Medicine ( IF 5.7 ) Pub Date : 2012-02-22 , DOI: 10.3892/ijmm.2012.920
Jung Eun Lee ₁ , Ae Sin Lee , Duk Hoon Kim , Yu Jin Jung , Sik Lee , Byung-Hyun Park , Sun Hwa Lee , Sung Kwang Park , Won Kim , Kyung Pyo Kang

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在炎症过程中，血管内皮细胞在白细胞运输中起重要作用。促炎细胞因子激活内皮细胞中细胞粘附分子的表达。Janus激酶（JAK）以及信号转导和转录激活剂（STAT）是重要的细胞内细胞因子信号传导分子，参与免疫反应。这项研究的目的是调查JAK3抑制作用对血管内皮细胞中肿瘤坏死因子（TNF）-α诱导的细胞粘附分子表达的影响，并评估JAK3对内毒素血症小鼠心肌血管通透性的治疗潜力。JAK3抑制剂JANEX-1降低了TNF-α诱导的细胞间粘附分子（ICAM）-1的表达，人脐静脉内皮细胞（HUVEC）中的VCAM（血管细胞粘附分子）-1和fractalkine。JANEX-1对这些细胞粘附分子表达的下调是通过抑制STAT3磷酸化和核因子-κB（NF-κB）活化来介导的。在内毒素血症小鼠中，用JANEX-1预处理不仅可以防止小动脉和毛细血管内皮细胞中LPS引起的心脏ICAM-1表达增加，而且还可以防止心肌血管渗漏。这些结果表明，JANEX-1对JAK / STAT通路的抑制可改善HUVEC中TNF-α诱导的细胞粘附分子的表达，并改善心肌血管通透性。JANEX-1对这些细胞粘附分子表达的下调是通过抑制STAT3磷酸化和核因子-κB（NF-κB）激活来介导的。在内毒素血症小鼠中，用JANEX-1预处理不仅可以防止小动脉和毛细血管内皮细胞中LPS引起的心脏ICAM-1表达增加，而且还可以防止心肌血管渗漏。这些结果表明，JANEX-1对JAK / STAT通路的抑制可改善HUVEC中TNF-α诱导的细胞粘附分子的表达，并改善心肌血管通透性。JANEX-1对这些细胞粘附分子表达的下调是通过抑制STAT3磷酸化和核因子-κB（NF-κB）活化来介导的。在内毒素血症小鼠中，用JANEX-1预处理不仅可以防止小动脉和毛细血管内皮细胞中LPS引起的心脏ICAM-1表达增加，而且还可以防止心肌血管渗漏。这些结果表明，JANEX-1抑制JAK / STAT通路可改善HUVEC中TNF-α诱导的细胞粘附分子的表达，并改善心肌血管通透性。

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Janex-1, a JAK3 inhibitor, ameliorates tumor necrosis factor-α-induced expression of cell adhesion molecules and improves myocardial vascular permeability in endotoxemic mice.

Vascular endothelial cells play an important role in leukocyte trafficking during the inflammatory process. Proinflammatory cytokines activate the expression of cell adhesion molecules in endothelial cells. Janus kinase (JAK) and signal transducer and activator of transcription (STAT) are important intracellular cytokine signaling molecules that are involved in immune responses. The purpose of this study was to investigate the effect of JAK3 inhibition on the expression of tumor necrosis factor (TNF)-α-induced cell adhesion molecules in vascular endothelial cells and to evaluate the therapeutic potential of JAK3 for myocardial vascular permeability in endotoxemic mice. A JAK3 inhibitor, JANEX-1, decreased the TNF-α-induced expression of intercellular adhesion molecule (ICAM)-1, VCAM (vascular cell adhesion molecule)-1 and fractalkine in human umbilical vein endothelial cells (HUVECs). The downregulation of the expression of these cell adhesion molecules by JANEX-1 was mediated via suppression of STAT3 phosphorylation and nuclear factor-κB (NF-κB) activation. In endotoxemic mice, pretreatment with JANEX-1 prevented not only an increase in the cardiac ICAM-1 expression by LPS in the arteriolar and capillary endothelial cells, but also myocardial vascular leakage. These results suggest that inhibition of the JAK/STAT pathway by JANEX-1 ameliorates the expression of TNF-α-induced cell adhesion molecules in HUVECs and improves myocardial vascular permeability.

更新日期：2019-11-01

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