JAK-STAT信号转导途径与中枢神经系统

作为一条新型信号转导通路 ,JAK STAT广泛参与细胞的生长、分化等过程。但目前对该通路的研究主要集中在造血及免疫系统 ,对其在中枢神经系统 (CNS)内的功能及作用机制尚没有完全阐明。本文对JAK STAT途径各成员在CNS内的表达、分布情况 ,以及该途径在CNS发育及病理状态下的功能变化进行了简要介绍     

Ulinastatin protects rats from sepsis-induced acute lung injury by suppressing the JAK-STAT3 pathway

Sepsis is usually accompanied by pulmonary inflammations, leading to acute lung injury. During this process, endogenous factors that play a regulatory role could be exploited to therapeutically alleviate such lethal tissue injury. Here, we showed that ulinastatin (UTI) administration could reduce lung tissue necrosis and swelling during sepsis in rats. UTI treatment also decreased the levels of inflammatory mediators both in the lung and in the serum. Mechanistically, we showed that the phosphorylation levels of JAK2 and STAT3 in the lung of UTI-treated rats were lower than control rats and were correlated with the decreased levels of inflammatory mediators. Taken together, these results demonstrate the protective role of UTI in sepsis-induced acute lung injury.     

JAK-STAT信号转导途径与中枢神经系统

作为一条新型信号转导通路,JAK－STAT广泛参与细胞的生长、分化等过程。但目前对该通路的研究主要集中在造血及免疫系统,对其在中枢神经系统（CNS）内的功能及作用机制的没有完全阐明。本文对JAK－STAT途径各成员在CNS内的表达、分布情况,以及该途径在CNS发育及病理状态下的功能变化进行了简要介绍。     

心肌JAK-STAT信号通路的研究进展

JAK-STAT信号通路介导心肌细胞的生长、存活和凋亡,并参与血管生成的调节,在心脏疾病的发生机制中发挥重要作用。压力负荷导致的心肌肥大、心力衰竭、缺血预处理诱导的心肌保护,以及缺血-再灌注引起的心功能障碍,都与这一信号通路密切相关。血管紧张素Ⅱ(ANGⅡ)与JAK-STAT信号通路相互作用加重缺血性心肌损伤;激活gpl30-STAT3信号通路对心力衰竭和缺血性心脏病的防治具有重要意义。     

LOX-1 pathway affects the extent of myocardial ischemia-reperfusion injury

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) was originally identified as a receptor for oxidized low-density lipoprotein predominantly expressed in endothelial cells. LOX-1 expression can be induced in cardiomyocytes and that activation of LOX-1 is involved in apoptosis. To investigate possible roles of LOX-1 in myocardial ischemia-reperfusion injury, rats were subjected to coronary artery ligation for 1h followed by reperfusion for 2h. Immunohistochemistry revealed that expression of LOX-1 in cardiac myocytes was induced following ischemia-reperfusion but not ischemia alone. Administration of anti-LOX-1 monoclonal antibody resulted in a nearly 50% reduction in myocardial infarction size compared with that of normal IgG or saline (P<0.05). These findings suggest that activation of the LOX-1 pathway is involved in determining the extent of myocardial ischemia-reperfusion injury and that inhibition of the LOX-1 pathway may provide a novel strategy for treatment of acute myocardial infarction in humans.     

Role of the JAK-STAT pathway in protection of hydrogen peroxide preconditioning against apoptosis induced by oxidative stress in PC12 cells

The aim of this study was to investigate the role of JAK-STAT pathway in the cytoprotection afforded by preconditioning with H₂O₂. It was shown that (1) Preconditioning with 100 μmol/L H₂O₂ can markedly protect PC12 cells against apoptosis and cytotoxicity induced by 300 μmol/L H₂O₂; (2) The expression and tyrosine phosphorylation of JAK2, not JAK1 were rapidly increased at 5 min after H₂O₂ preconditioning; (3) The expression of STAT1 and STAT3 were significantly increased at 15 min after H₂O₂ preconditioning, and the pTyr-STAT1 and pTyr-STAT3 were markedly increased at 60 min after H₂O₂ preconditioning; (4) Pretreatment with the JAK inhibitor AG-490 (10 μmol/L) 20 min before H₂O₂ preconditioning blocked not only the activation of JAK2, STAT1 and STAT3, but also the cytoprotection of H₂O₂ preconditioning against apoptosis and cytotoxicity induced by oxidative stress. These findings suggested that preconditioning with H₂O₂ activated the JAK-STAT pathway that played an important role in the cytoprotection induced by H₂O₂ preconditioning.     

钙敏感受体通过JNK途径参与内毒素心肌损伤*

目的: 观察内毒素所致的心肌损伤中,钙敏感受体(CaSR)对c-Jun氨基末端激酶 (JNK)途径的影响。方法: 腹腔注射内毒素(5 mg/kg)制作新生大鼠内毒素心肌损伤模型,Wistar新生大鼠随机分为6组:对照组、内毒素组、CaSR激动剂组、CaSR抑制剂组、JNK抑制剂组、CaSR抑制剂+JNK抑制剂组。HE染色观察心肌形态, 测定血清乳酸脱氢酶(LDH)含量,PCR检测IL-6的mRNA表达,Western blot检测CaSR及JNK的蛋白表达。结果: 与对照组相比,内毒素组心肌损伤加重,LDH含量、IL-6的mRNA表达、CaSR和JNK的蛋白表达均明显增加(P＜0.05)。与内毒素组比较,CaSR激动剂组心肌损伤加重,LDH含量、IL-6的mRNA表达、CaSR和JNK的蛋白表达增加(P＜0.05); CaSR抑制剂组心肌损伤减轻,LDH含量、CaSR和JNK的蛋白表达减少(P＜0.05);JNK抑制剂组心肌损伤进一步减轻,LDH含量、IL-6的mRNA表达、CaSR和JNK的蛋白表达均减少(P＜0.05);CaSR抑制剂+JNK抑制剂组心肌损伤明显减轻,LDH含量、IL-6的mRNA表达、CaSR和JNK的蛋白表达进一步减少(P＜0.05)。结论: CaSR可能通过JNK途径参与内毒素所致的心肌损伤。     

Role of sodium-calcium exchanger in the myocardial protection against ischemia-reperfusion injury

Present study was aimed at investigation into the role of sodium-calcium exchanger (NCX) in myocardial ischemia-reperfusion injury and ischemic preconditioning (IPC). Experiments were performed in vivo rat model of regional myocardial ischemia-reperfusion. It was shown that inhibition of reverse mode of NCX with selective blocker KB-R7943 at a dose of 10 mg/kg resulted in significant decrease in occurrence and severity of ischemic ventricular tachyarrhythmias. Furthermore, administration of KB-R7943 caused potentiation of the antiarrhythmic effect exerted by single episode of IPC. However, KB-R7943 exerted no effect on myocardial infarction size nor affected infarction size limitation by IPC. In conclusion, inhibition of reverse mode of NCX conferred significant antiarrhythmic effect against ischemic rhythm disorders but it was ineffective in terms of infarction size limitation.     

Galectin-3 exerts cytokine-like regulatory actions through the JAK-STAT pathway

Galectin-3, a β-galactoside-binding lectin, has been proposed to have multifaceted functions in various pathophysiological conditions. However, the characteristics of galectin-3 and its molecular mechanisms of action are still largely unknown. In this study, we show that galectin-3 exerts cytokine-like regulatory actions in rat and mouse brain-resident immune cells. Both the expression of galectin-3 and its secretion into the extracellular compartment were significantly enhanced in glia under IFN-γ-stimulated, inflamed conditions. After exposure to galectin-3, glial cells produced high levels of proinflammatory mediators and exhibited activated properties. Notably, within minutes after exposure to galectin-3, JAK2 and STAT1, STAT3, and STAT5 showed considerable enhancement of tyrosine phosphorylation; thereafter, downstream events of STAT signaling were also significantly enhanced. Treatment of the cells with pharmacological inhibitors of JAK2 reduced the galectin-3-stimulated increases of inflammatory mediators. Using IFN-γ receptor 1-deficient mice, we further found that IFN-γR 1 might be required for galectin-3-dependent activation of the JAK-STAT cascade. However, galectin-3 significantly induced phosphorylation of STATs in glial cells from IFN-γ-deficient mice, suggesting that IFN-γ does not mediate activation of STATs. Collectively, our findings suggest that galectin-3 acts as an endogenous danger signaling molecule under pathological conditions in the brain, providing a potential explanation for the molecular basis of galectin-3-associated pathological events.     

The JAK-STAT signaling pathway: input and output integration

Universal and essential to cytokine receptor signaling, the JAK-STAT pathway is one of the best understood signal transduction cascades. Almost 40 cytokine receptors signal through combinations of four JAK and seven STAT family members, suggesting commonality across the JAK-STAT signaling system. Despite intense study, there remain substantial gaps in understanding how the cascades are activated and regulated. Using the examples of the IL-6 and IL-10 receptors, I will discuss how diverse outcomes in gene expression result from regulatory events that effect the JAK1-STAT3 pathway, common to both receptors. I also consider receptor preferences by different STATs and interpretive problems in the use of STAT-deficient cells and mice. Finally, I consider how the suppressor of cytokine signaling (SOCS) proteins regulate the quality and quantity of STAT signals from cytokine receptors. New data suggests that SOCS proteins introduce additional diversity into the JAK-STAT pathway by adjusting the output of activated STATs that alters downstream gene activation.     

Role of endothelial dysfunction in the pathogenesis of reperfusion injury after myocardial ischemia

Endothelial dysfunction occurs after myocardial ischemia and reperfusion characterized by a marked reduction in endothelium-dependent relaxation (EDR) due to reduced release or action of endothelium-derived relaxing factor (EDRF). This reduced EDR occurs in coronary rings isolated from cats 2.5 min after reperfusion and in isolated perfused cat hearts 2.5 min after reperfusion. No decrease in EDR occurs before reperfusion in either preparation, suggesting that this impairment in EDR occurs during reperfusion. The decrease in EDR occurs soon after the generation of superoxide radicals by the reperfused coronary endothelium. Accumulation of neutrophils and myocardial cell injury does not occur until 3-4.5 h after reperfusion. Thus, endothelial generation of superoxide radicals acts as a trigger mechanism for endothelial dysfunction which is then amplified by neutrophil adherence and diapedesis into the ischemic region enhancing post-reperfusion ischemic injury. Agents that preserve endothelial function or inhibit neutrophil activation (e.g., superoxide dismutase, prostacyclin analogs, TGF-beta, antibodies to adhesive proteins) can protect against endothelial dysfunction and myocardial injury, if administered before reperfusion.     

Human leptin signaling in human peripheral blood mononuclear cells: activation of the JAK-STAT pathway

Leptin is an adipocyte-secreted hormone that centrally regulates weight control. However, the leptin receptor is expressed not only in the central nervous system, but also in other systems, such as reproductive, hematopoietic, and immune tissues, suggesting various roles in addition to the regulation of food intake and energy expenditure. The leptin receptor bears homology to members of the class I cytokine receptor family. Leptin has previously been shown to enhance cytokine production by murine peritoneal macrophages and human circulating monocytes, where human leptin promotes activation and proliferation. We have recently found that the leptin receptor is expressed not only in monocytes but also in both CD4(+) and CD8(+) T lymphocytes. Besides, leptin enhances proliferation and activation of T lymphocytes when they are costimulated by PHA or Con A. In this paper, we have studied the signal transduction of the leptin receptor in peripheral blood mononuclear cells. We found that leptin stimulation activates the JAK-STAT signaling pathway. More specifically, we found that JAK-2/3 and STAT-3 are activated by tyrosine phosphorylation upon leptin stimulation. Moreover, leptin stimulated tyrosine phosphorylation of the RNA binding protein Sam68 and its association with STAT-3. These effects were dose-dependent (0.1-10 nM) and transient (5-30 min). We also observed the leptin stimulated translocation of activated STAT-3 from the cytoplasm to the nucleus. These results indicate that human leptin receptor in circulating mononuclear cells has the signaling capacity to activate JAK-STAT cascade. This pathway may mediate, at least in part, the action of human leptin in human peripheral blood mononuclear cells.