骨关节炎与细胞因子TNF-α、IL-6关系的研究进展

骨关节炎又称退行性骨关节炎,是中老年人常见、多发的骨关节病,其病因及发病机制尚未完全明确。目前认为细胞因子通过各种机制调节软骨细胞的功能活动,在关节软骨退变中起到了重要的作用。本文就与骨关节炎相关的细胞因子-分解性细胞因子TNF-α和调节性细胞因子IL-6在骨关节炎发病过程中的作用作一综述,认为对细胞因子如TNF-α、IL-6的生物学作深入研究必将有助于对骨关节炎发生机理的进一步认识,为骨关节炎的治疗及疾病的预后,提供科学的理论依据和可行的方法指导。     

白介素-18与临床疾病相关性研究进展

白介素-18(IL-18)为近几年发现的一种新的白介素类细胞因子，是一种重要的免疫调节因子。IL-18有增强免疫、抗肿瘤等作用。但是另一方面IL-18也与一些自身免疫性疾病、变态反应性疾病等密切相关。IL-18不论是在加强机体的免疫力方面，还是在许多疾病的治疗中都具有重要的基础研究及临床应用前景。现对近年来IL-18与疾病相关性研究进展作一综述。     

结核性胸腔积液中两种免疫抑制性细胞因子的研究

目的 研究结核性胸腔积液中两种免疫抑制性细胞因子肿瘤坏死因子-β1（TGF—β1）、白介素-10（IL-10）在结核病免疫发病机制中的作用,为发展免疫疗法提供依据。方法用双抗体夹心酶联免疫吸附法（ELISA）试剂盒检测39例结核性胸腔积液患者（初治组29例,复治组10例;Ⅱ型结核病1例,Ⅲ型28例,Ⅳ型10例）胸水中和血清中TGF-β1、IL-10水平。对每种细胞因子胸水中和血清中含量及两组胸水及血清中细胞因子含量进行显著性检验,并进行相关性分析;对治疗过程中10例Ⅲ型病人和5例Ⅳ型病人X线片示进展期到好转期这些细胞因子在胸水中的变化进行观测。结果除复治组胸水、血清中TGF-β1含量无显著差异外,两种细胞因子胸水与血清中含量均有显著差异;两种细胞因子水平没有相关关系。治疗好转过程中,两种细胞因子的变化虽有一定的规律可循,但不是一成不变的。结论TGF-β1和IL-10参与了抗结核分枝杆菌（Mtb）感染的免疫过程;开展免疫治疗时应该综合考虑机体的免疫状态,某种细胞因子的作用不是对所有病人都有效,与体内细胞因子间的平衡有关。     

流式细胞微球芯片捕获技术在食管癌患者Th1/Th2细胞因子谱型分析中的意义

T辅助细胞Ⅰ类细胞因子主要包括白介素2(IL-2)、α-肿瘤坏死因子(TNF-α)和γ-干扰素(IFN-α)等，Ⅱ类细胞因子主要包括IL-4、IL-6和IL-10等。它们是机体调节和维持细胞免疫与体液免疫平衡的重要分子。研究发现，肿瘤患者外周血Ⅰ／Ⅱ类细胞因子水平异常，可直接影响肿瘤的发生、发展与预后。本研究通过测定食管癌患者血浆Ⅰ／Ⅱ类细胞因子含量，分析细胞因子谱型变化特点及与临床的关系，以了解食管癌患者Ⅰ／Ⅱ类细胞因子的免疫调节功能状况，为临床生物治疗食管癌提供个体化治疗依据。     

慢性乙型肝炎患者IL-12，IL-18测定的意义

研究证实,机体免疫功能紊乱,尤其是T淋巴细胞亚群与细胞因子的调节失调与慢性肝病的发生发展密切相关。本文探讨慢性乙型肝炎患者IL-12、IL-18测定的意义,现报道如下。     

IL-12家族抗肿瘤作用的研究进展

IL-12家族是一类结构相似、共价结合的异二聚体细胞因子家族,目前其主要成员包括 IL-12、IL-23、IL-27和 IL-35。IL-12由 p35和 p40两个亚基通过二硫键结合形成,是细胞免疫应答过程中的关键调节因子,在激活 NK 细胞、T 细胞,并诱使其分泌大量 IFN-γ,抑制肿瘤血管生成等方面具有重要的作用。IL-23由 p40和 p19亚基以二硫键结合形成,在抗肿瘤及抗自身免疫病中发挥着重要作用。IL-27由 p28和 EBI3亚基通过二硫键结合形成,在维持机体免疫系统的自身稳定、抗感染及抗肿瘤中起着重要的作用。IL-35由 p35和 EBI3亚基通过二硫键结合形成,在抑制效应 T 细胞增殖、Th17细胞分化和 IL-17的合成方面发挥重要作用。随着 IL-12家族成员的丰富,IL-12家族成员的功能研究也越来越深入,近年来大量研究认为 IL-12家族在肿瘤的发生、发展中具有至关重要的作用,因此,本文就 IL-12家族与其抗肿瘤作用的研究作一综述。     

运动中的一些免疫学问题

运动可对机体免疫及内分泌系统产生广泛影响。针对运动中中性白细胞,细胞因子的变化和意义以及免疫与神经内分泌系统之间的相互作用作一概述。     

不同方法制备浓缩血小板保存过程中细胞因子含量的检测

目的 研究不同方法制备的浓缩血小板在保存过程中细胞因子含量的变化。方法 应用PRP法、BC法及SD法制备浓缩血小板，并于常规条件下保存，间隔取样检测保存期内细胞因子如IL-1β、IL-6、IL-8、TNF-α等的含量。结果 浓缩血小板在保存期内随保存时间的延长，细胞因子含量升高，且浓缩血小板中细胞因子含量与其中混杂的白细胞数直接相关。结论 细胞因子在非溶血性发热输血反应发生中可能起协同作用。     

病毒性心肌炎小儿血清IL-2、IL-4、IL-6浓度的检测

病毒性心肌炎是病毒侵犯心脏所引起的以心肌细胞变性、坏死和间质性炎症等心肌炎性病变为主要表现的疾病。在小儿中发病率较高，并呈上升趋势，临床表现轻重不一，严重危害小儿的健康。其发病机制尚不完全清楚，与病毒感染后直接作用于心脏及病毒感染后的免疫损伤有关。本文检测了病毒性心肌炎患儿血清白介素IL-2（IL-2）、白介素IL-4（IL-4）、白介素IL-6（IL-6）的浓度。探讨细胞因子在病毒性心肌炎时对机体的作用。     

血清IFN-γ、IL-18、IL-4和IL-13水平与过敏性哮喘的相关性分析

过敏性哮喘是临床常见和多发的呼吸系统疾病之一,已经成为世界范围内严重的公共卫生问题。但是过敏性哮喘的病因仍不完全清楚。近年来国内外诸多研究发现 Th1/Th2平衡失调以及细胞因子都在过敏反应中发挥重要作用。为了探讨细胞因子在过敏性哮喘发生发展中的作用,检测60例过敏性哮喘患者及52例健康人外周血中IFN-γ、IL-18、IL-4和IL-13的表达,作分析比较。结果报告如下。     

NMDA Receptor Modulates Spinal Iron Accumulation Via Activating DMT1(-)IRE in Remifentanil-Induced Hyperalgesia

N-methyl-D-aspartate (NMDA) receptor activation is known to be critical in remifentanil-induced hyperalgesia. Evidence indicates that iron accumulation participates in NMDA neurotoxicity. This study aims to investigate the role of iron accumulation in remifentanil-induced hyperalgesia. Remifentanil was delivered intravenously in rats to induce hyperalgesia. The NMDA receptor antagonist MK-801 was intrathecally administrated. The levels of divalent metal transporter 1 without iron-responsive element [DMT1(-)IRE] and iron were detected. Behavior testing was performed in DMT1(-)IRE knockdown rats and rats treated with iron chelator DFO. Meanwhile, the spinal dorsal horn neurons were cultured and transfected with DMT1(-)IRE siRNA, and then respectively incubated with remifentanil and MK-801. The levels of intracellular Ca²⁺ and iron were assessed by fluorescence imaging. Our data revealed that spinal DMT1(-)IRE and iron content significantly increased in remifentanil-treated rats, and MK-801 inhibited the enhancements. DMT1(-)IRE knockdown and DFO prevented against remifentanil-induced hyperalgesia. Notably, the levels of Ca²⁺ and iron increased in remifentanil-incubated neurons, and these growths can be blocked by MK-801. DMT1(-)IRE knockdown attenuated iron accumulation but did not influence Ca²⁺ influx. This study suggests that DMT1(-)IRE-mediated iron accumulation is likely to be the downstream event following NMDA receptor activation and Ca²⁺ influx, contributing to remifentanil-induced hyperalgesia.PerspectiveRemifentanil-induced hyperalgesia is common even when used within clinical accepted doses. This study presents that aberrant iron accumulation is involved in the development of remifentanil-induced hyperalgesia in vivo and in vitro. Iron chelation may be a potential therapeutic strategy for the prevention of hyperalgesia in populations at high risk.     

Iron as spirit of life to share under monopoly

Any independent life requires iron to survive. Whereas iron deficiency causes oxygen insufficiency, excess iron is a risk for cancer, generating a double-edged sword. Iron metabolism is strictly regulated via specific systems, including iron-responsive element (IRE)/iron regulatory proteins (IRPs) and the corresponding ubiquitin ligase FBXL5. Here we briefly reflect the history of bioiron research and describe major recent advancements. Ferroptosis, a newly coined Fe(II)-dependent regulated necrosis, is providing huge impact on science. Carcinogenesis is a process to acquire ferroptosis-resistance and ferroptosis is preferred in cancer therapy due to immunogenicity. Poly(rC)-binding proteins 1/2 (PCBP1/2) were identified as major cytosolic Fe(II) chaperone proteins. The mechanism how cells retrieve stored iron in ferritin cores was unraveled as ferritinophagy, a form of autophagy. Of note, ferroptosis may exploit ferritinophagy during the progression. Recently, we discovered that cellular ferritin secretion is through extracellular vesicles (EVs) escorted by CD63 under the regulation of IRE/IRP system. Furthermore, this process was abused in asbestos-induced mesothelial carcinogenesis. In summary, cellular iron metabolism is tightly regulated by multi-system organizations as surplus iron is shared through ferritin in EVs among neighbor and distant cells in need. However, various noxious stimuli dramatically promote cellular iron uptake/storage, which may result in ferroptosis.     

Iron supplementation affects the production of pro-inflammatory cytokines in IL-10 deficient mice

BACKGROUND: Iron supplements may increase disease activity in inflammatory bowel disease through the production of the hydroxyl radical because of its catalytic activity in the Fenton reaction. The purpose of this study was to assess the effect of dietary and locally administered iron in the IL-10 knock-out (-/-) mouse, a model of chronic inflammatory bowel disease. MATERIALS AND METHODS: IL10-/- and wild-type mice received a standard or a high-iron diet (35 mg kg(-1) ferrosulphate vs. 500 mg kg(-1) ferrosulphate) after weaning. After 4 weeks the mice were sacrificed. Furthermore, a group of adult IL-10 knock-out mice was given three iron-containing enema's (0.2 mL of 1 mM ferrous-ammonium sulphate) or phosphate buffered saline. These mice were sacrificed after 1 week. Production of pro-inflammatory cytokines by colon tissue cultures, haematological parameters and histology was determined to assess inflammatory activity. RESULTS: Oral as well as rectal administration of iron resulted in increased pro-inflammatory cytokine production in IL-10-/- mice. Neutrophil counts in IL10-/- on a high iron diet increased as well. No enhanced colonic inflammation was noted on histology after iron supplementation. CONCLUSION: We conclude that dietary or topical administered iron increases pro-inflammatory cytokine production in the colon of IL10-/- mice. No significant increase of histological intestinal inflammation was observed.     

Granulocyte function in patients with L-ferritin iron-responsive element (IRE) 39C-->T-positive hereditary hyperferritinaemia-cataract syndrome

BACKGROUND: Hereditary hyperferritinaemia-cataract syndrome (HHCS) is an autosomal dominant trait associated with mutations in the iron responsive element (IRE) of the ferritin light-chain (L-ferritin) gene. Patients typically show elevated serum ferritin concentrations without iron overload and a bilateral cataract. Hyperferritinaemia can be associated with granulocyte dysfunction in patients with thalassemia beta and in haemodialysis patients. The effect of increased L-ferritin levels on granulocyte function in patients with HHCS is unknown. MATERIAL AND METHODS: We examined glucose uptake, oxidative burst, chemotaxis, phagocytosis, apoptosis and intracellular calcium concentrations in polymorphonuclear leucocytes (PMNLs) of five affected members of a family with HHCS and in five healthy individuals matched for age and gender. RESULTS: Mutation testing revealed a 39C-->T transition in IRE in all five patients with HHCS. Serum ferritin levels of patients ranged between 907 and 2030 microg L(-1), respectively. In comparison with healthy individuals, PMNLs of patients with HHCS showed a significant increase in PMA-mediated stimulation of the oxidative burst, as well as a significantly higher stimulation of glucose uptake but no difference with respect to chemotaxis, phagocytosis, apoptosis and intracellular calcium concentrations. CONCLUSION: In summary, our study suggests that hyperferritinaemia in patients with IRE 39C-->T-positive HHCS is associated with activation of PMNLs but not with disturbance of fundamental PMNL function.     

甲状腺激素T3影响K562细胞转铁蛋白受体和铁蛋白表达的分子机制研究

目的 探讨甲状腺激素T3对白血病细胞K562转铁蛋白受体(TfR)和铁蛋白(Fn)表达的调控作用及其可能的机制。方法 采用流式细胞术和放射免疫法分别检测TfR和Fn的表达水平，用RNA/蛋白带移动分析法测定铁调节蛋白(IRP)与铁反应元件(IRE)的结合活性。应用RT—PCR方法半定量分析TfR和Fn的mRNA水平。结果 T3对K562细胞TfR的表达无明显作用，而以不同浓度的T3处理细胞后使Fn的表达增加，其中当T3为100nmol/L和200nmol/L时，与空白对照组相比，差异有显性(P＜0．05)。T3能减少IRP/IRE的结合活性，且以T3为50nmol/L时减少最为明显。不同浓度的T3在不同的作用时间内均能提高H—FnmRNA水平，而对TfRmRNA水平无显影响。结论 T3可增加细胞Fn的表达，而对TfR的表达无明显调控作用，其机制除包含转录后的调节外，可能还具有转录水平的调控作用。     

Divergent Effects of PERK and IRE1 Signaling on Cell Viability

Protein misfolding in the endoplasmic reticulum (ER) activates a set of intracellular signaling pathways, collectively termed the Unfolded Protein Response (UPR). UPR signaling promotes cell survival by reducing misfolded protein levels. If homeostasis cannot be restored, UPR signaling promotes cell death. The molecular basis for the switch between prosurvival and proapoptotic UPR function is poorly understood. The ER-resident proteins, PERK and IRE1, control two key UPR signaling pathways. Protein misfolding concomitantly activates PERK and IRE1 and has clouded insight into their contributions toward life or death cell fates. Here, we employed chemical-genetic strategies to activate individually PERK or IRE1 uncoupled from protein misfolding. We found that sustained PERK signaling impaired cell proliferation and promoted apoptosis. By contrast, equivalent durations of IRE1 signaling enhanced cell proliferation without promoting cell death. These results demonstrate that extended PERK and IRE1 signaling have opposite effects on cell viability. Differential activation of PERK and IRE1 may determine life or death decisions after ER protein misfolding.     

Serum concentrations of dehydroepiandrosterone and dehydroepiandrosterone sulfate and their relation to cytokine production during and after normal pregnancy

Background: Since dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) have been suggested to have immunoregulatory effects, changes in the levels of these substances during and after pregnancy might affect the maternal immune system. We examined serum concentrations of DHEA and DHEAS, and cytokine production during pregnancy and after delivery. Methods: The subjects were 73 normal pregnant, 76 normal postpartum and 30 normal non-pregnant women. Whole-blood was stimulated with phorbol 12-myristate 13-acetate (PMA) and ionomycin and the levels of cytokines in the supernatant were measured using enzyme-linked immunosorbent assay (ELISA). DHEA and DHEAS were measured using ELISA and gas chromatography–mass spectrometry (GC-MS), respectively. Results: The serum DHEA levels increased in the first and in the second trimesters and decreased after delivery until 11 months postpartum. DHEAS levels were decreased in the second and in the third trimesters and returned to non-pregnant levels after pregnancy. All measured cytokines (IFN-γ, IL-2, IL-4 and IL-10) were decreased during pregnancy and subsequently increased postpartum. We found significant negative correlations between DHEA and cytokine levels. Conclusions: Increase of serum DHEA in the first and the second trimesters may suppress immune reaction during pregnancy, while a decrease of DHEA after delivery may induce postpartum enhancement of the maternal immune system. DHEA may be involved in modifying the maternal immune responses during and after pregnancy.     

Pharmacological regulation of the insulin receptor signaling pathway mimics insulin action in cells transduced with viral vectors

Diabetes mellitus derives from either insulin deficiency (type I) or resistance (type II). Homozygous mutations in the insulin receptor (IR) gene cause the rare leprechaunism and Rabson-Mendenhall syndromes, severe forms of hyperinsulinemic insulin resistance for which no therapy is currently available. Systems have been developed that allow protein-protein interactions to be brought under the control of small-molecule dimerizer drugs. As a potential tool to rescue glucose homeostasis at will in both insulin and insulin receptor deficiencies, we developed a recombinant chimeric insulin receptor (LFv2IRE) that can be homodimerized and activated by the small-molecule dimerizer AP20187. In HepG2 cells transduced with adeno-associated viral (AAV) vectors encoding LFv2IRE, AP20187 induces LFv2IRE homodimerization and transphosphorylation minutes after drug administration, resulting in the phosphorylation of a canonical substrate of the insulin receptor tyrosine kinase, IRS-1. AP20187 activation of LFv2IRE is dependent on the dose of drug and the amount of chimeric receptor expressed in AAV-transduced cells. Finally, AP20187-dependent activation of LFv2IRE results in insulin-like effects, such as induction of glycogen synthase activity and cellular proliferation. In vivo LFv2IRE transduction of insulin target tissues followed by AP20187 dosing may represent a therapeutic strategy to be tested in animal models of insulin resistance due to insulin receptor deficiency or of type I diabetes. This system may also represent a useful tool to dissect in vivo the independent contribution of insulin target tissues to hormone action.     

不可逆电穿孔技术治疗恶性肿瘤研究进展

不可逆电穿孔(IRE)技术通过施加电场使细胞发生凋亡而不产生热效应、不损伤脉管结构,与化学治疗和/或免疫疗法联合使用时疗效更佳,是治疗恶性肿瘤的新手段。本文就IRE技术原理及其治疗恶性肿瘤研究进展进行综述。