雷公藤红素对肥胖型哮喘小鼠Th17细胞和气道炎症的影响

张慧, 曾泽宇, 王磊, 林西西, 张维溪

中国药学杂志 ›› 2019, Vol. 54 ›› Issue (7) : 542-548.

PDF(3223 KB)
PDF(3223 KB)
中国药学杂志 ›› 2019, Vol. 54 ›› Issue (7) : 542-548. DOI: 10.11669/cpj.2019.07.005
·论 著·

雷公藤红素对肥胖型哮喘小鼠Th17细胞和气道炎症的影响

  • 张慧a, 曾泽宇a, 王磊a, 林西西b, 张维溪a*
作者信息 +

Effect of Celastrol on Airway Inflammation and Th17 Cells in Obese Asthmatic Mice

  • ZHANGHuia, ZENGZe-yua, WANGLeia, LINXi-xib, ZHANGWei-xia*
Author information +
文章历史 +

摘要

目的 探讨雷公藤红素对肥胖型哮喘小鼠辅助性T细胞17(Th17)细胞和气道炎症的影响。方法 随机将30只雄性C57BL/6小鼠分成5组,包括正常对照组、卵白蛋白(ovalbumin, OVA)致敏哮喘组、肥胖组、肥胖型哮喘组、雷公藤红素干预组。通过HE染色评估各组小鼠肺组织气道炎性细胞浸润及气道形态变化情况;免疫组织化学染色半定量分析白细胞介素(IL)-17A蛋白的表达情况;应用流式细胞术(FCM)检测小鼠脾脏Th17细胞与CD4+T淋巴细胞的比值;运用实时荧光定量聚合酶链反应法(QRT-PCR)检测各组小鼠肺组织中IL-17A mRNA的表达水平;应用酶联免疫吸附试验(ELISA)检测各组小鼠血清IL-17A水平。结果 HE染色结果显示,哮喘组、肥胖型哮喘组小鼠可见大量的炎症细胞浸润于小气道、小血管周围,肥胖组小鼠可见少量炎症性细胞浸润,雷公藤红素干预组小鼠炎症性细胞浸润明显减少,正常对照组未见炎性细胞浸润。哮喘组、肥胖组、肥胖型哮喘组小鼠肺组织中IL-17A光密度均值、IL-17A mRNA表达水平及血清中IL-17A含量显著高于正常对照组(P均<0.01),而雷公藤红素干预组小鼠肺组织中IL-17A光密度均值、IL-17A mRNA表达水平及血清中IL-17A含量较肥胖型哮喘组显著降低,差异有统计学意义(P<0.01)。哮喘组、肥胖组、肥胖型哮喘组小鼠脾脏分离淋巴细胞中Th17细胞/CD4+T细胞比值均较对照组明显增高,差异有统计学意义(P 均<0.01),雷公藤红素干预组小鼠Th17细胞/CD4+T细胞的比值显著低于肥胖型哮喘组,差异具有显著性(P<0.01)。结论 雷公藤红素对肥胖型哮喘小鼠体内Th17细胞及Th17细胞因子的表达有抑制作用,改善肥胖哮喘气道炎症。

Abstract

OBJECTIVE To study the effect of celastrol on the airway inflammation and Th17 cells in obese asthmatic mice.METHODS Thirty male C57BL/6 mices were randomly divided into five groups sham group, ovalbumin(OVA)+DMSO group, diet-induced obesity(DIO)+DMSO group, DIO+OVA+DMSO group, DIO+OVA+celastrol group. H&E staining was used to examine histological changes in the lungs. Immunohistochemistry was used to observe IL-17A protein in lung tissues; flow cytometry was used to detect the proportion of Th17 cells in CD4+T cells. The expression of IL-17A mRNA in lung was examined by quantitative real-time RT-PCR, while concentration of cytokines IL-17A in serum was assessed by standardized sandwich ELISA. RESULTS OVA+DMSO group and DIO+OVA+DMSO group showed significant higher inflammatory cells infiltration in the airways and small perivascular spaces of the lungs compared with sham group. DIO+DMSO group showed less inflammatory cells infiltration than DIO+OVA+DMSO group. However, DIO+OVA+celastrol group showed significantly reduced inflammatory cells infiltration. The expression of IL-17A in lung tissues, IL-17A mRNA in mice lung and serum IL-17A level from DIO+OVA+DMSO group, OVA+DMSO group, and DIO+DMSO group significantly increased compared with sham group (P<0.01). However, the expression of IL-17A in lung tissues, IL-17A mRNA in mice lung and serum IL-17A level significantly decreased in DIO+OVA+celastrol group compared with DIO+OVA+DMSO group (P<0.01). A significant increase of Th17 cells in CD4+T cell of mice spleen was found in OVA+DMSO group, DIO+DMSO group and DIO+OVA+DMSO group compared with sham group (P<0.01). Though, DIO+OVA +celastrol group revealed a significant reduction of Th17 cells compared with DIO +OVA +DMSO group (P<0.01).CONCLUTION Celastrol administration downregulates Th17 cells, decreases IL-17A production in obese asthmatic mice. Celastrol effectively alleviates airway inflammation in obese asthatic mice.

关键词

雷公藤红素 / 哮喘 / 肥胖 / 气道炎症 / 辅助性T细胞17

Key words

celastrol / asthma / obese / airway inflammation / T help cell 17

引用本文

导出引用
张慧, 曾泽宇, 王磊, 林西西, 张维溪. 雷公藤红素对肥胖型哮喘小鼠Th17细胞和气道炎症的影响[J]. 中国药学杂志, 2019, 54(7): 542-548 https://doi.org/10.11669/cpj.2019.07.005
ZHANGHui, ZENGZe-yu, WANGLei, LINXi-xi, ZHANGWei-xi. Effect of Celastrol on Airway Inflammation and Th17 Cells in Obese Asthmatic Mice[J]. Chinese Pharmaceutical Journal, 2019, 54(7): 542-548 https://doi.org/10.11669/cpj.2019.07.005
中图分类号: R725.6   

参考文献

[1] PERMAUL P, KANCHONGKITTIPHON W, PHIPATANAKUL W. Childhood asthma and obesity- what is the true link [J]. Ann Allergy Asthma Immunol, 2014, 113(3):244-246.
[2] WENZEL S E. Asthma phenotypes: the evolution from clinical to molecular approaches [J]. Nat Med, 2012, 18(5):716-725.
[3] ANO S, MORISHIMA Y, ISHII Y, et al. Transcription factors GATA-3 and RORgammat are important for determining the phenotype of allergic airway inflammation in a murine model of asthma [J]. J Immunol, 2013, 190(3):1056-1065.
[4] MORISHIMA Y, ANO S, ISHII Y, et al. Th17-associated cytokines as a therapeutic target for steroid-insensitive asthma [J]. Clin Dev Immunol, 2013, 2013:609395.
[5] ENDO Y, ASOU H K, MATSUGAE N, et al. Obesity Drives Th17 Cell Differentiation by Inducing the Lipid Metabolic Kinase, ACC1 [J]. Cell Rep, 2015, 12(6):1042-1055.
[6] KIM D Y, PARK J W, JEOUNG D, et al. Celastrol suppresses allergen-induced airway inflammation in a mouse allergic asthma model [J]. Eur J Pharmacol, 2009, 612 (1-3):98-105.
[7] LIU J, LEE J, SALAZAR HERNANDEZ M A, et al. Treatment of obesity with celastrol [J]. Cell, 2015, 161(5):999-1011.
[8] KIM Y, KIM K, LEE H, et al. Celastrol binds to ERK and inhibits FcepsilonRI signaling to exert an anti-allergic effect [J]. Eur J Pharmacol, 2009, 612(1-3):131-142.
[9] WINER S, PALTSER G, CHAN Y, et al. Obesity predisposes to Th17 bias[J]. Eur J Immunol, 2009, 39(9):2629-2635.
[10] LIANG L, HUR J, KANG J Y, et al. Effect of the anti-IL-17 antibody on allergic inflammation in an obesity-related asthma model [J]. Korean J Intern Med, 2018,33(6):1220-1223.
[11] ENDO Y, YOKOTE K, NAKAYAMA T, et al. The obesity-related pathology and Th17 cells [J]. Cell Mol Life Sci, 2017, 74(7):1231-1245.
[12] LUCZYNSKI W, GRUBCZAK K, MONIUSZKO M, et al. Elevated levels of Th17 cells in children with central obesity [J]. Scand J Clin Lab Invest, 2015, 75(7):595-601.
[13] SUMARAC-DUMANOVIC M, STEVANOVIC D, LIUBIC A, et al. Increased activity of interleukin-23 / interleukin-17 proinflammatory axis in obese women [J]. Int J Obes (Lond), 2009, 33(1):151-156.
[14] MCLAUGHLIN T, LIU L F, LAMENDOLA C, et al. T-cell profile in adipose tissue is associated with insulin resistance and systemic inflammation in humans [J]. Arterioscler Thromb Vasc Biol, 2014, 34(12):2637-2643.
[15] YAN X, HUANG Y, WANG H, et al. Maternal obesity induces sustained inflammation in both fetal and offspring large intestine of sheep [J]. Inflamm Bowel Dis, 2011, 17(7):1513-1522.
[16] SCHINDLER T I, WAGMER J J, GOEDICKE-FRITZ S, et al. TH17 Cell Frequency in Peripheral Blood Is Elevated in Overweight Children without Chronic Inflammatory Diseases [J]. Front Immunol, 2017, 8:1543.
[17] BETTELLI E, KORN T, KUCHROO V K. Th17: the third member of the effector T cell trilogy [J]. Curr Opin Immunol, 2007, 19(6):652-657.
[18] KANELLOPOULOU C, MULJO S A. Fine-tuning Th17 cells: to be or not to be pathogenic [J]. Immunity, 2016, 44(6):1241-1243.
[19] LI K, WANG Z, CAO Y, et al. The study of the ratio and distribution of Th17 cells and Tc17 cells in asthmatic patients and the mouse model [J]. Asian Pac J Allergy Immunol, 2013, 31(2):125-131.
[20] ELAIDY S M, ESSAWY S S, HUSSAIN M A, et al. Modulation of the IL-23/IL-17 axis by fenofibrate ameliorates the ovalbumin/lipopolysaccharide-induced airway inflammation and bronchial asthma in rats [J]. Naunyn Schmiedebergs Arch Pharmacol, 2018, 391(3):309-321.
[21] JOEAN O, HUEBER A, FELLER F, et al. Suppression of Th17-polarized airway inflammation by rapamycin [J]. Sci Rep, 2017, 7(1):15336.
[22] LIU C, ZHU L, FUKUDA K, et al. The flavonoid cyanidin blocks binding of the cytokine interleukin-17A to the IL-17RA subunit to alleviate inflammation in vivo [J]. Sci Signal, 2017, 10(467).pii:eaaf8823.
[23] ZHANG W, ZHANG X, SHENG A, et al. γ-Secretase gamma-Secretase Inhibitor Alleviates Acute Airway Inflammation of Allergic Asthma in Mice by Downregulating Th17 Cell Differentiation [J]. Mediators Inflamm, 2015, 2015, 258168.
[24] MCKINLEY L, ALCORN J F, PETERSON A, et al. TH17 cells mediate steroid-resistant airway inflammation and airway hyperresponsiveness in mice [J]. J Immunol, 2008, 181(6):4089-4097.
[25] ZHANG J, SHAN J, CHEN X, et al. Celastrol mediates Th17 and Treg cell generation via metabolic signaling[J]. Biochem Biophys Res Commun, 2018, 497(3):883-889.
[26] ASTRY B, VENKATESHA S H, LAURENCE A, et al. Celastrol, a Chinese herbal compound, controls autoimmune inflammation by altering the balance of pathogenic and regulatory T cells in the target organ [J]. Clin Immunol, 2015, 157(2):228-238.
[27] WANG Y, CAO L, XU L M, et al. Celastrol Ameliorates EAE Induction by Suppressing Pathogenic T Cell Responses in the Peripheral and Central Nervous Systems [J]. J Neuroimmune Pharmacol, 2015, 10(3):506-516.

基金

国家自然科学基金面上基金项目资助(81770030);浙江省卫生高层次创新人才项目资助;温州市公益性科技计划项目资助(Y20160226)
PDF(3223 KB)

Accesses

Citation

Detail

段落导航
相关文章

/