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白介素34的结构及其与相关疾病的关系

更新时间:2020-03-03 15:31点击:

2.2 IL-34与肝炎、肝纤维化、肝硬化

  SHENG-TAO CHENG等[10]证实IL-34的降低可能与乙型肝炎病毒(The hepatitis B virus, HBV)的复制有关,是HBV治疗的潜在靶点。慢性丙型肝炎病毒(Chronic hepatitis C virus, HCV)感染高纤维化阶段的患者血清中巨噬细胞集落刺激因子(M-CSF)和IL-34的水平高于低纤维化阶段患者及健康受试者[11]。IL-34可诱导单核细胞分化为促纤维化的巨噬细胞(M?),通过激活M?的FAK和ERK1/2信号,促进细胞增殖和趋化迁移,从而触发I型胶原的合成。人IL-13极化的M-CSF/IL-34-M?和GM-CSF-M?有着明显的区别,每种细胞都有部分小鼠M2a细胞(即IL-13极化的巨噬细胞)的特征,只有M-CSF/IL-34-M?表现出促纤维化的表型,IL-34是否也参与其他病因的肝纤维化和其他器官的纤维化仍有待探索。通过基因表达谱和生物信息学分析,已证实miR-28-5p的表达与肝癌细胞的转移潜能呈负相关,IL-34作为miR-28-5p的直接靶点,由miR-28-5p介导的调节肿瘤微环境的信号通路通过IL-34调控巨噬细胞在肿瘤床上的顺序再吸收和浸润[12]。体内外研究表明,IL-34对肝癌生长和转移的影响是通过肿瘤相关巨噬细胞(tumor-associated macrophage,TAMS)的募集和浸润来实现的,TAMS的促肿瘤作用包括促进血管生成和增强肿瘤细胞及巨噬细胞的增殖、迁移和侵袭[13,14],从而形成miR-28-5p-IL-34-巨噬细胞正反馈环,其在肝癌转移中发挥重要作用。miR-28-5p联合IL-34及TAMS可作为肝癌根治性切除患者的一项新的预后指标。

  2.3 IL-34与类风湿性关节炎

  相关研究表明,类风湿性关节炎(rheumatoid arthritis, RA)患者滑膜、血清及滑液中IL-34的表达增加[7,15,16,17]。血清IL-34表达水平与急性时相反应物或IL-6水平有关,滑膜IL-34表达与RA滑膜炎的病理严重程度有关[15,16,17]。SISI YANG等人[18]将类风湿性关节炎(Rheumatoid arthritis, RA)患者按28-节点疾病活动评分(28-joint Disease Activity Score, DAS 28)分为2组:中、高疾病活动组(DAS 28≥3.2)和低疾病活动组(DAS 28<3.2),结果:DAS28(DAS28≥3.2)组患者的平均滑液IL-34(synovial fluid IL34, SFIL-34)和microRNA 21(miR-21)的表达水平显着高于DAS28(DAS28<3.2)组,且miR-21与SFIL-34在DAS28(DAS28≥3.2)组中的表达水平呈显着的正相关,即上调的IL-34以剂量依赖性的方式增强STA T3的活化,通过与CSF-1R的结合增加miR-21的表达,从而调节Bcl-2/Bax比率的变化,有利于RA中滑膜成纤维细胞(fibroblast-like synovial cells, FLS)的抗凋亡作用。MARGUERITE CHEMEL等人[19]证实骨形成蛋白-2(bone morphogenetic protein-2, BMP-2)和转化生长因子-β1(transforming growth factor--β1, TGF-β1)两种细胞因子能够分别通过活化素受体样激酶(activin receptor-like kinase, ALK)1和ALK5通路抑制IL-34基因的表达。多元回归分析发现RA患者血清IL-34浓度与类风湿因子及抗环瓜氨酸抗体滴度显着相关,但与X线损害程度和全身骨质疏松没有任何相关性[16]。

  2.4 IL-34与糖尿病、肥胖

  肥胖妇女血清IL-34浓度约为正常人的2倍。胃旁路手术(Roux-en-Y gastric bypass, RYGB)诱导的体重减轻后,血清IL-34水平显着降低。EUN-JU CHANG等人[20]发现IL-34mRNA在皮下脂肪组织(SAT)和内脏脂肪组织(VAT)中都有表达,后者的表达水平是正常的2倍。在脂肪组织中,IL-34mRNA在基质/血管(stroma/vascular, SV)细胞中表达略高于脂肪细胞,差异无统计学意义。此外,血清IL-34不仅与肥胖参数(如体质指数BMI和腹部脂肪面积)呈显着正相关,而且还与胰岛素抵抗和慢性炎症密切相关[20]。数据显示血清IL-34与胰岛素抵抗的参数稳态模型评估(HOMA-IR)有很强的正相关性[20];在脂肪形成过程中,补充IL-34可增加脂肪的积累,这也可能导致脂肪细胞肥大,最终导致胰岛素抵抗。此外IL-34还在人脂肪细胞中显着抑制胰岛素刺激的葡萄糖转运,然而也必须要考虑到糖尿病患者的临床状况。KATARZYNA ZORENA等[21]认为IL-34对于糖尿病并发症发生发展风险的预测相比C-反应蛋白有更大的辨识能力,但目前没有研究可以确定IL-34在2型糖尿病患者发生长期并发症的危险因素中的截断值。此外,巨噬细胞-CM、肿瘤坏死因子α(tumor necrosis factorα, TNFα)、IL-1β释放的典型促炎细胞因子,可显着诱导脂肪细胞IL-34的表达和分泌。虽然IL-34是巨噬细胞增殖和分化的重要调节因子,但在巨噬细胞向脂肪组织的浸润中还没有发现IL-34作用的证据。因此,仍需要获得较大样本的2型糖尿病患者和高危人群的进一步调查研究,来深入了解IL-34的炎症潜能。

  2.5 IL-34与肺癌

  MUHAMMAD BAGHDADI等[22]报道认为肺癌细胞产生的IL-34是化疗耐药的驱动因子。肺癌细胞长期暴露于细胞毒剂后导致NF-κB活化增强,从而诱导耐药细胞中IL-34的表达,进而促进单核细胞分化为M2极化的巨噬细胞,这在肿瘤化疗耐药的发生发展中起到了至关重要的作用[6,22,23,24]。受化学耐药细胞上清液刺激的巨噬细胞表现出 C/EBPβ(CCAAT/enhancer-binding protein β)磷酸化水平的增强,其由IL-34诱导的CSF1R/AKT信号通路激活介导,以保护肿瘤在化疗条件下免受免疫攻击、维持肿瘤微环境(the tumor microenvironment, TME)的稳态,由此提示IL-34是未来治疗策略中克服化疗耐药的有效靶点。

  2.6 IL-34与肾脏疾病

  JEA-HYUN BAEK等[25]检测到IL-34可促进肾脏缺血-再灌注损伤后巨噬细胞介导的管状上皮细胞的破坏;IL-34在急性期管状上皮细胞中表达上调,在慢性期持续升高,在对缺血-再灌注损伤最敏感的髓质中表达最高。IL-34并不直接募集单核细胞,而是增加肾内炎症,从而趋化循环髓样细胞到发炎的肾脏。最近在大脑神经祖细胞和胶质细胞中发现了第二个白细胞介素-34受体蛋白质酪氨酸磷酸酶-ζ(protein-tyrosine phosphatase-ζ, PTP-ζ),这可以解释IL-34和CSF-1的某些功能不同。肾内PTP-ζ主要由管型上皮细胞表达并与IL-34结合,并在肾缺血-再灌注损伤慢性期相比急性期表达更强。剖析ptp-ζ在肾脏疾病中的作用可能是复杂的,因为这种受体通过多种配体的作用结合并发出信号[26],包括肝素结合生长因子、肝素结合细胞因子[27]、细胞表面接触蛋白[28]、细胞外基质蛋白tenascin-R[29]。介于IL-34和IL-34受体在小鼠和人肾脏中的表达均被上调,可初步推测IL-34介导移植肾排斥反应和其他形式的肾损伤。大量实验数据表明,靶向IL-34在肾脏和循环中可能是一项抑制急性肾损伤和慢性肾脏疾病潜在的治疗策略。

  2.7 IL-34与骨髓细胞

  WEI等[30,31]通过将IL-34置于CSF 1启动子下,制备转基因小鼠模型来比较CSF-1和IL-34对髓系细胞的调节作用;其同BAUD’HUIN等[5]的体外培养均提示IL-34由成骨细胞高表达,并在调节破骨发生中起着重要作用。IL-34不能单独诱导破骨细胞形成,需与RANKL联合才可以形成具有骨吸收活性的破骨细胞[32]。然而,由于缺乏有关小鼠和人类IL-34蛋白相对组织丰度和循环水平的信息,很难推测其在这些方面的作用是否仅局限于小鼠。在癌症中,IL-34被发现通过促进血管生成和巨噬细胞的吸收从而促进骨肉瘤的肿瘤进展和转移过程[33]。大量的实验研究结果和数据将IL-34的作用直接与骨生理学联系起来,为潜在的临床应用开辟了新的可能性。

  2.8 IL-34与其他疾病

  在干燥综合征患者的唾液腺和冠心病患者的循环中,IL-34的表达上调[34,35]。强直性脊柱炎患者血清IL-34与其炎症性背痛有关,其基线水平可作为X线检查的预后因素[36]。YU G等[37]报告称IL-34在甲型流感病毒感染患者中升高,并可在炎症级联中由IL-22诱导。耳部白介素-34的表达受深皮巨噬细胞和表皮朗格汉斯细胞CSF-1介导的信号通路的控制[38,39,40],这些细胞直接合成IL-34或诱导其他细胞以旁分泌的方式合成IL-34。

  3 展望

  作为重要的促炎因子,IL-34广泛参与抗体分泌、γ-干扰素的产生、细胞增殖以及分化等多种生物学过程。随着IL-34在常见疾病研究中不断展开,使得IL-34日益成为人们研究的热点,因此更加深入的探究IL-34在疾病中的功能和作用机制,将为多种疾病尤其是炎性疾病的治疗提供扎实的理论基础和新的靶点。

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