生长分化因子15在LPS诱导的帕金森病模型中的保护作用及机制

doi:10.6040/j.issn.1671-7554.0.2022.0102

摘要/Abstract

摘要： 目的探究生长分化因子15(GDF15)在脂多糖(LPS)诱导的帕金森病神经炎症中的保护作用及其机制。方法筛选LPS作用于BV2细胞的合适时间,分为空白组、3 h组、6 h组、12 h组和24 h组;筛选LPS作用于BV2细胞的合适浓度,分为空白组、0.5 mg/mL组、1 mg/mL组和2 mg/mL组;探究外源性GDF15作用时,BV2细胞分为空白组、LPS组和LPS+GDF15组;实验动物分为野生小鼠对照组(WT组)、野生小鼠模型组(WT+LPS组)和GDF15敲除小鼠模型组(KO+LPS组)。采用Western blotting法检测信号转导和转录激活因子3(STAT3)/核转录因子κB(NF-κB)/细胞外信号调节激酶(ERK)蛋白表达水平,采用qPCR法检测肿瘤坏死因子(TNF-α)、白细胞介素(IL-1β)、诱导型一氧化氮合酶(iNOS)、环氧合酶-2(COX-2)的表达水平,使用显微镜观察BV2小胶质细胞形态变化。结果外源性GDF15通过抑制STAT3/NF-κB/ERK信号通路,可降低TNF-α、IL-1β、iNOS、COX-2等炎症分子的表达,GDF15敲除小鼠模型组黑质、纹状体的炎症反应增强,TNF-α、IL-1β、iNOS、COX-2等炎症分子的表达升高。结论 GDF15在帕金森病的炎症模型中可以通过STAT3/NF-κB/ERK信号通路降低炎症因子的表达,GDF15通过抑制炎症因子的分泌进而在帕金森病的进展中发挥保护作用,为帕金森病的防治提供新的靶点。

关键词: 生长分化因子15, 帕金森病, 神经炎症, 信号通路, 小鼠

Abstract: Objective To investigate the protective effect and mechanism of growth differentiation factor 15(GDF15)in lipopolysaccharide(LPS)induced neuroinflammation associated with Parkinsons disease. Methods To explore the optimum time of LPS, BV2 cells were divided into blank, 3 h, 6 h, 12 h and 24 h groups; to explore the optimum concentration of LPS, BV2 cells were divided into blank, 0.5, 1 and 2mg/mL groups; to explore the effect of GDF15, BV2 cells were divided into blank, LPS and LPS+GDF15 groups. The mice were divided into WT, WT+LPS and KO-LPS group. The protein expressions of STAT3, NF-κB and ERK were detected with Western blotting. The mRNA expressions of TNF-α, IL-1β, iNOS and COX-2 were detected with qPCR. The effect of GDF15 on the morphology of LPS-induced BV2 cells was observed with a microscope. Results GDF-15 suppressed the expressions of TNF-α, IL-1β, iNOS and COX-2 by inhibiting the STAT3/NF-κB/ERK signaling pathway. In the substantia nigra and striatum of the GDF15 knockout mice, the expressions of TNF-α, IL-1β, iNOS and COX-2 increased. Conclusion GDF15 can attenuate the expressions of TNF-α, IL-1β, iNOS and COX-2 through STAT3/NF-κB/ERK signaling pathway, indicating it is a protective factor in the progression of Parkinsons disease. It can provide a new therapeutic target for the prevention and treatment of this disease.

Key words: Growth differentiation factor 15, Parkinsons disease, Neuroinflammation, Signal pathway, Mice

中图分类号:

R574

张秀芳,李沛铮,张博涵,孙丛丛,刘艺鸣. 生长分化因子15在LPS诱导的帕金森病模型中的保护作用及机制[J]. 山东大学学报 (医学版), 2022, 60(5): 1-7.

ZHANG Xiufang, LI Peizheng, ZHANG Bohan, SUN Congcong, LIU Yiming. Protective effect and mechanism of growth differentiation factor-15 in LPS-induced models of Parkinsons disease[J]. Journal of Shandong University (Health Sciences), 2022, 60(5): 1-7.

参考文献

[1] Bloem BR, Okun MS, Klein C. Parkinsons disease [J]. Lancet, 2021, 397(10291): 2284-2303.
[2] Pajares M, Rojo AI, Manda G, et al. Inflammation in Parkinsons disease: mechanisms and therapeutic implications [J]. Cells, 2020, 9(7): 1687.
[3] Chrysoula M, Maria S, Efthimios D, et al. Neurodegeneration and inflammation-an interesting interplay in Parkinsons disease [J]. Int J Mol Sci, 2020, 21(22): 8421.
[4] McGeer PL, Itagaki S, Boyes BE, et al. Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinsons and Alzheimers disease brains [J]. Neurology, 1988, 38(8): 1285-1291.
[5] Ouchi Y, Yagi S, Yokokura M, et al. Neuroinflammation in the living brain of Parkinsons disease [J]. Park Relat Disord, 2009, 15(Suppl 3): 200-204.
[6] Nagatsu T, Mogi M, Ichinose H, et al. Cytokines in Parkinsons disease [J]. J Neural Transm Suppl, 2000(58): 143-151.
[7] Huang B, Liu J, Meng T, et al. Polydatin prevents lipopolysaccharide(LPS)-induced parkinsons disease via regulation of the AKT/GSK3β-Nrf2/NF-κB signaling axis [J]. Front Immunol, 2018, 9: 2527. doi: 10.3389/fimmu.2018.02527.
[8] Lai JL, Liu YH, Liu C, et al. Indirubin inhibits LPS-induced inflammation via TLR4 abrogation mediated by the NF-kB and MAPK signaling pathways [J]. Inflammation, 2017, 40(1): 1-12.
[9] Corre J, Hébraud B, Bourin P. Concise review: growth differentiation factor 15 in pathology: a clinical role? [J]. Stem Cells Transl Med, 2013, 2(12): 946-952.
[10] Breit SN, Johnen H, Cook AD, et al. The TGF-β superfamily cytokine, MIC-1/GDF15: a pleotrophic cytokine with roles in inflammation, cancer and metabolism [J]. Growth Factors, 2011, 29(5): 187-195.
[11] Unsicker K, Spittau B, Krieglstein K. The multiple facets of the TGF-β family cytokine growth/differentiation factor-15/macrophage inhibitory cytokine-1 [J]. Cytokine Growth Factor Rev, 2013, 24(4): 373-384.
[12] Yao XM, Wang D, Zhang L, et al. Serum growth differentiation factor 15 in parkinson disease [J]. Neuro Degener Dis, 2017, 17(6): 251-260.
[13] Machado V, Haas SJ, von Bohlen Und Halbach O, et al. Growth/differentiation factor-15 deficiency compromises dopaminergic neuron survival and microglial response in the 6-hydroxydopamine mouse model of Parkinsons disease [J]. Neurobiol Dis, 2016, 88: 1-15. doi: 10.1016/j.nbd.2015.12.016.
[14] Machado V, Gilsbach R, Das R, et al. Gdf-15 deficiency does not alter vulnerability of nigrostriatal dopaminergic system in MPTP-intoxicated mice [J]. Cell Tissue Res, 2016, 365(2): 209-223.
[15] Nam HY, Nam JH, Yoon G, et al. Ibrutinib suppresses LPS-induced neuroinflammatory responses in BV2 microglial cells and wild-type mice [J]. J Neuroinflammation, 2018, 15(1): 271.
[16] Yang L, Zhou R, Tong Y, et al. Neuroprotection by dihydrotestosterone in LPS-induced neuroinflammation [J]. Neurobiol Dis, 2020, 140: 104814. doi: 10.1016/j.nbd.2020.104814.
[17] Wu SY, Pan BS, Tsai SF, et al. BDNF reverses aging-related microglial activation [J]. J Neuroinflammation, 2020, 17(1): 210.
[18] Zhang R, Rupa EJ, Zheng S, et al. Panos-fermented extract-mediated nanoemulsion: preparation, characterization, and in vitro anti-inflammatory effects on RAW 264.7 cells [J]. Molecules, 2021, 27(1): 218.
[19] McGeer PL, Itagaki S, Boyes BE, et al. Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinsons and Alzheimers disease brains [J]. Neurology, 1988, 38(8): 1285-1291.
[20] Jiang WW, Zhang ZZ, He PP, et al. Emerging roles of growth differentiation factor-15 in brain disorders(Review)[J]. Exp Ther Med, 2021, 22(5): 1270.
[21] Conte M, Martucci M, Chiariello A, et al. Mitochondria, immunosenescence and inflammaging: a role for mitokines? [J]. Semin Immunopathol, 2020, 42(5): 607-617.
[22] Gliozzi M, Scicchitano M, Bosco F, et al. Modulation of nitric oxide synthases by oxidized LDLs: role in vascular inflammation and atherosclerosis development [J]. Int J Mol Sci, 2019, 20(13): 3294-3294.
[23] Yu H, Pardoll D, Jove R. STATs in cancer inflammation and immunity: a leading role for STAT3 [J]. Nat Rev Cancer, 2009, 9(11): 798-809.
[24] Samidurai M, Ramasamy VS, Jo J. Β-amyloid inhibits hippocampal LTP through TNFR/IKK/NF-κb pathway [J]. Neurol Res, 2018, 40(4): 268-276.
[25] Jones SV, Kounatidis I. Nuclear factor-kappa B and alzheimer disease, unifying genetic and environmental risk factors from cell to humans [J]. Front Immunol, 2017, 8: 1805. doi: 10.3389/fimmu.2017.01805.
[26] Sun Y, Liu WZ, Liu T, et al. Signaling pathway of MAPK/ERK in cell proliferation, differentiation, migration, senescence and apoptosis [J]. J Recept Signal Transduct Res, 2015, 35(6): 600-604.
[27] Cargnello M, Roux PP. Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases [J]. Microbiol Mol Biol Rev, 2011, 75(1): 50-83.
[28] Mogi M, Togari A, Kondo T, et al. Caspase activities and tumor necrosis factor receptor R1(p55)level are elevated in the substantia nigra from Parkinsonian brain [J]. J Neural Transm, 2000, 107(3): 335-341.
[29] Zhang Q, Lenardo MJ, Baltimore D. 30 years of NF-κB: a blossoming of relevance to human pathobiology [J]. Cell, 2017, 168(1/2): 37-57.

相关文章 15

[1]	杨晓倩季静刘娜郭冬梅崔癉. 三氯化铁及络合铁的抗银屑病作用研究[J]. 山东大学学报(医学版), 2209, 47(6): 114-117.
[2]	段淑红刘凯尹海燕赵世斗刘丰韬. 凝集素受体WGA、RCA和ECL在过量维甲酸致昆明小鼠腭裂发生中的作用[J]. 山东大学学报(医学版), 2209, 47(6): 47-.
[3]	邹品衡,陈添果,胡康,李伟才. 过表达miR-27a对急性脑梗死大鼠海马神经元损伤的影响及其机制[J]. 山东大学学报 (医学版), 2022, 60(9): 59-66.
[4]	张秉芬,周胜红,王哲. 延龄草皂苷通过抑制TGF-β/Smad3与Wnt/β-catenin信号通路改善大鼠肺纤维化[J]. 山东大学学报 (医学版), 2022, 60(8): 23-29.
[5]	相宇娇,刘强,刘璐,石艳. 原发免疫性血小板减少症树突状细胞异常免疫反应机制[J]. 山东大学学报 (医学版), 2022, 60(7): 89-97.
[6]	刘敏,张玉超,马小莉,刘昕宇,孙露,左丹,刘元涛. 孤核受体NR4A1在H₂O₂诱导小鼠肾脏足细胞损伤中的作用[J]. 山东大学学报 (医学版), 2022, 60(5): 16-21.
[7]	申晓畅,孙一卿,颜磊,赵兴波. 芳基烃受体核转位因子样蛋白2在子宫内膜癌中的表达[J]. 山东大学学报 (医学版), 2022, 60(5): 74-80.
[8]	虎娜,孙苗,邢莎莎,许丹霞,海小明,马玲,杨丽,勉昱琛,何瑞,陈冬梅,马会明. 月见草油抵抗多囊卵巢综合征大鼠卵巢氧化应激[J]. 山东大学学报 (医学版), 2022, 60(5): 22-30.
[9]	赵海龙,王皓,方雨晴,毛飞,赵张宁,田祥奇,徐新荣,王敏,李秀华. 增服艾地苯醌对34例帕金森病抑郁患者的疗效观察[J]. 山东大学学报 (医学版), 2022, 60(4): 38-44.
[10]	刘丽雯,马俊,李沛铮,张秀芳,刘艺鸣. 128例帕金森病照料者负担及影响因素[J]. 山东大学学报 (医学版), 2022, 60(4): 45-49.
[11]	菅天孜,陈诺,李理想,李延青,李艳. D-甘露糖和葡萄糖在溃疡性结肠炎小鼠中的作用[J]. 山东大学学报 (医学版), 2022, 60(3): 24-28.
[12]	曾媛媛,杨东鹏,董柱,张本,曹一秋,王晓武. 川芎嗪对野百合碱诱导大鼠肺动脉高压的影响及机制[J]. 山东大学学报 (医学版), 2022, 60(11): 63-69.
[13]	李娜,郭增丽,迟令懿,杨立卓,马志勇,付志婕. 甲醛对嗜酸性粒细胞EOL-1的急性损伤作用机制[J]. 山东大学学报 (医学版), 2022, 60(11): 54-62.
[14]	封海岗,刘国文,曹洪. 干扰MAD2L1基因表达对乳腺癌细胞凋亡的影响及机制[J]. 山东大学学报 (医学版), 2022, 60(10): 9-16.
[15]	王芳,陈华,商丽红,李茹月,李咏梅,杨玉娥,哈春芳. U0126对子宫内膜异位症大鼠MEK/ERK/NF-κB通路及增殖侵袭的影响[J]. 山东大学学报 (医学版), 2021, 59(9): 148-154.

多维度评价

Viewed

Full text

Abstract

Cited

Shared

Discussed