Association between miR‑126, miR‑21, inflammatory factors and T lymphocyte apoptosis in septic rats

Zou,Qi; Yang,Mei; Yu,Meiling; Liu,Cheng

doi:10.3892/mco.2021.2368

Association between miR‑126, miR‑21, inflammatory factors and T lymphocyte apoptosis in septic rats

Authors:
- Qi Zou
- Mei Yang
- Meiling Yu
- Cheng Liu
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Affiliations: Department of Critical Care Medicine, The First Affiliated Hospital of Bengbu Medical College, Anhui, Bengbu 233004, P.R. China, Department of Pediatrics, The First Affiliated Hospital of Bengbu Medical College, Anhui, Bengbu 233004, P.R. China, Department of Pharmacy, The First Affiliated Hospital of Bengbu Medical College, Anhui, Bengbu 233004, P.R. China
Published online on: August 8, 2021 https://doi.org/10.3892/mco.2021.2368
Article Number: 206

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Abstract

MicroRNAs (miRs) serve an important role in regulating expression levels of inflammatory factors but the underlying mechanism is still unclear. The present study aimed to observe miR‑126 and miR‑21 expression and apoptosis in T lymphocytes and to analyze their association with cytokine release in septic rats. The septic model rats were given intraperitoneal lipopolysaccharide (LPS) and divided into 0, 12, 24, 48 and 72 h groups. Peripheral blood was collected from each group to isolate T lymphocytes. The expression levels of miR‑126 and miR‑21 in T lymphocytes were observed, as well as cytokine release and apoptosis. Finally, the association between miR‑126, miR‑21, cytokines and apoptosis in T lymphocytes was analyzed. The release of TNF‑α and IL‑6 in septic rats was initially elevated but then decreased. miR‑126 and miR‑21 levels in T lymphocytes in septic rats were lower than those of NC rats. miR‑126 and miR‑21 initially decreased and then increased, whereas of apoptosis of T lymphocytes increased and then decreased, in septic rats. The expression of miR‑126 was positively correlated with that of miR‑21 (r=0.316; P=0.029) and negatively correlated with that of TNF‑α (r=‑0.480; P=0.001) and IL‑6 (r=‑0.626; P<0.001), as well as the apoptotic rate of T lymphocytes (r=‑0.377; P=0.008). Furthermore, expression levels of miR‑126 were negatively corrlated with caspase‑3 expression levels (r=‑0.606; P<0.001) and activity (r=‑0.541; P<0.001). There was a negative correlation between miR‑21 and levels of TNF‑α (r=‑0.311; P=0.032) and IL‑6 (r=‑0.439; P=0.002), as well as caspase‑3 expression (r=‑0.398; P=0.005) and activity (r=‑0.378; P=0.008). However, there miR‑126 expression was not correlated with apoptotic rate of T lymphocytes. Altered expression levels of miR‑126 and miR‑21 reflected the severity of inflammatory response and indicated levels of T lymphocyte apoptosis in septic rats.

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1	Shankar-Hari M, Phillips GS, Levy ML, Seymour CW, Liu VX, Deutschman CS, Angus DC, Rubenfeld GD and Singer M: Sepsis Definitions Task Force. Developing a new definition and assessing new clinical criteria for septic shock: For the third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA. 315:775–787. 2016.PubMed/NCBI View Article : Google Scholar
2	Fleischmann C, Scherag A, Adhikari NK, Hartog CS, Tsaganos T, Schlattmann P, Angus DC and Reinhart K: International Forum of Acute Care Trialists. Assessment of global incidence and mortality of hospital-treated sepsis. Current estimates and limitations. Am J Respir Crit Care Med. 193:259–272. 2016.PubMed/NCBI View Article : Google Scholar
3	Gotts JE and Matthay MA: Sepsis: Pathophysiology and clinical management. BMJ. 353(i1585)2016.PubMed/NCBI View Article : Google Scholar
4	van der Poll T, van de Veerdonk FL, Scicluna BP and Netea MG: The immunopathology of sepsis and potential therapeutic targets. Nat Rev Immunol. 17:407–420. 2017.PubMed/NCBI View Article : Google Scholar
5	Huang M, Cai S and Su J: The pathogenesis of sepsis and potential therapeutic targets. Int J Mol Sci. 20(5376)2019.PubMed/NCBI View Article : Google Scholar
6	Rizzo AN and Dudek SM: Endothelial glycocalyx repair: Building a wall to protect the lung during sepsis. Am J Respir Cell Mol Biol. 56:687–688. 2017.PubMed/NCBI View Article : Google Scholar
7	Rimmele T, Payen D, Cantaluppi V, Marshall J, Gomez H, Gomez A, Murray P and Kellum JA: ADQI XIV Workgroup. Immune cell phenotype and function in sepsis. Shock. 45:282–291. 2016.PubMed/NCBI View Article : Google Scholar
8	Delano MJ and Ward PA: The immune system's role in sepsis progression, resolution, and long-term outcome. Immunol Rev. 274:330–353. 2016.PubMed/NCBI View Article : Google Scholar
9	Hotchkiss RS, Monneret G and Payen D: Sepsis-induced immunosuppression: From cellular dysfunctions to immunotherapy. Nat Rev Immunol. 13:862–874. 2013.PubMed/NCBI View Article : Google Scholar
10	Hart M, Walch-Ruckheim B, Krammes L, Kehl T, Rheinheimer S, Tänzer T, Glombitza B, Sester M, Lenhof HP, Keller A and Meese E: MiR-34a as hub of T cell regulation networks. J Immunother Cancer. 7(187)2019.PubMed/NCBI View Article : Google Scholar
11	Deng JN, Li YQ, Liu Y, Li Q, Hu Y, Xu JQ, Sun TY and Xie LX: Exosomes derived from plasma of septic patients inhibit apoptosis of T lymphocytes by down-regulating bad via hsa-miR-7-5p. Biochem Biophys Res Commun. 513:958–966. 2019.PubMed/NCBI View Article : Google Scholar
12	Pandey RK, Sundar S and Prajapati VK: Differential expression of miRNA regulates t cell differentiation and plasticity during visceral leishmaniasis infection. Front Microbiol. 7(206)2016.PubMed/NCBI View Article : Google Scholar
13	Chu F, Hu Y, Zhou Y, Guo M, Lu J, Zheng W, Xu H, Zhao J and Xu L: MicroRNA-126 deficiency enhanced the activation and function of CD4⁺ T cells by elevating IRS-1 pathway. Clin Exp Immunol. 191:166–179. 2018.PubMed/NCBI View Article : Google Scholar
14	Ding S, Zheng Y, Xu Y, Zhao X and Zhong C: MiR-21/PTEN signaling modulates the chemo-sensitivity to 5-fluorouracil in human lung adenocarcinoma A549 cells. Int J Clin Exp Pathol. 12:2339–2352. 2019.PubMed/NCBI
15	Ruan Q, Wang P, Wang T, Qi J, Wei M, Wang S, Fan T, Johnson D, Wan X, Shi W, et al: MicroRNA-21 regulates T-cell apoptosis by directly targeting the tumor suppressor gene Tipe2. Cell Death Dis. 5(e1095)2014.PubMed/NCBI View Article : Google Scholar
16	Ando Y, Yang GX, Kenny TP, Kawata K, Zhang W, Huang W, Leung PS, Lian ZX, Okazaki K, Ansari AA, et al: Overexpression of microRNA-21 is associated with elevated pro-inflammatory cytokines in dominant-negative TGF-β receptor type II mouse. J Autoimmun. 41:111–119. 2013.PubMed/NCBI View Article : Google Scholar
17	Zheng Z, Xu PP, Wang L, Zhao HJ, Weng XQ, Zhong HJ, Qu B, Xiong J, Zhao Y, Wang XF, et al: MiR21 sensitized B-lymphoma cells to ABT-199 via ICOS/ICOSL-mediated interaction of Treg cells with endothelial cells. J Exp Clin Cancer Res. 36(82)2017.PubMed/NCBI View Article : Google Scholar
18	Teteloshvili N, Smigielska-Czepiel K, Kroesen BJ, Brouwer E, Kluiver J, Boots AM and van den Berg A: T-cell activation induces dynamic changes in miRNA expression patterns in CD4 and CD8 T-cell subsets. Microrna. 4:117–122. 2015.PubMed/NCBI View Article : Google Scholar
19	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001.PubMed/NCBI View Article : Google Scholar
20	Balk RA: Systemic inflammatory response syndrome (SIRS): Where did it come from and is it still relevant today? Virulence. 5:20–26. 2014.PubMed/NCBI View Article : Google Scholar
21	Song GY, Chung CS, Chaudry IH and Ayala A: Immune suppression in polymicrobial sepsis: Differential regulation of Th1 and Th2 responses by p38 MAPK. J Surg Res. 91:141–146. 2000.PubMed/NCBI View Article : Google Scholar
22	Cheng Z, Abrams ST, Toh J, Wang SS, Wang Z, Yu Q, Yu W, Toh CH and Wang G: The critical roles and mechanisms of immune cell death in sepsis. Front Immunol. 11(1918)2020.PubMed/NCBI View Article : Google Scholar
23	Pool R, Gomez H and Kellum JA: Mechanisms of organ dysfunction in sepsis. Crit Care Clin. 34:63–80. 2018.PubMed/NCBI View Article : Google Scholar
24	Chen J, Xuan J, Gu YT, Shi KS, Xie JJ, Chen JX, Zheng ZM, Chen Y, Chen XB, Wu YS, et al: Celastrol reduces IL-1β induced matrix catabolism, oxidative stress and inflammation in human nucleus pulposus cells and attenuates rat intervertebral disc degeneration in vivo. Biomed Pharmacother. 91:208–219. 2017.PubMed/NCBI View Article : Google Scholar
25	Xie Z, Zhang H, Wang J, Li Z, Qiu C and Sun K: LIN28B-AS1-IGF2BP1 association is required for LPS-induced NFκB activation and pro-inflammatory responses in human macrophages and monocytes. Biochem Biophys Res Commun. 519:525–532. 2019.PubMed/NCBI View Article : Google Scholar
26	Sun J, Shi S, Wang Q, Yu K and Wang R: Continuous hemodiafiltration therapy reduces damage of multi-organs by ameliorating of HMGB1/TLR4/NFκB in a dog sepsis model. Int J Clin Exp Pathol. 8:1555–1564. 2015.PubMed/NCBI
27	Hamers L, Kox M and Pickkers P: Sepsis-induced immunoparalysis: Mechanisms, markers, and treatment options. Minerva Anestesiol. 81:426–439. 2015.PubMed/NCBI
28	Ono S, Tsujimoto H, Hiraki S and Aosasa S: Mechanisms of sepsis-induced immunosuppression and immunological modification therapies for sepsis. Ann Gastroenterol Surg. 2:351–358. 2018.PubMed/NCBI View Article : Google Scholar
29	Luan YY, Yao YM, Xiao XZ and Sheng ZY: Insights into the apoptotic death of immune cells in sepsis. J Interferon Cytokine Res. 35:17–22. 2015.PubMed/NCBI View Article : Google Scholar
30	Kim JS, Kim SJ and Lee SM: Genipin attenuates sepsis-induced immunosuppression through inhibition of T lymphocyte apoptosis. Int Immunopharmacol. 27:15–23. 2015.PubMed/NCBI View Article : Google Scholar
31	Atmatzidis S, Koutelidakis IM, Chatzimavroudis G, Kotsaki A, Louis K, Pistiki A, Savva A, Antonopoulou A, Atmatzidis K and Giamarellos-Bourboulis EJ: Detrimental effect of apoptosis of lymphocytes at an early time point of experimental abdominal sepsis. BMC Infect Dis. 11(321)2011.PubMed/NCBI View Article : Google Scholar
32	Yin F, Zhang F, Liu S and Ning B: The therapeutic effect of high-volume hemofiltration on sepsis: A systematic review and meta-analysis. Ann Transl Med. 8(488)2020.PubMed/NCBI View Article : Google Scholar
33	Luan YY, Yin CF, Qin QH, Dong N, Zhu XM, Sheng ZY, Zhang QH and Yao YM: Effect of regulatory T cells on promoting apoptosis of T lymphocyte and its regulatory mechanism in sepsis. J Interferon Cytokine Res. 35:969–980. 2015.PubMed/NCBI View Article : Google Scholar
34	Zheng G, Pan M, Li Z, Xiang W and Jin W: Effects of vitamin D on apoptosis of T-lymphocyte subsets in neonatal sepsis. Exp Ther Med. 16:629–634. 2018.PubMed/NCBI View Article : Google Scholar
35	Oberholzer C, Oberholzer A, Clare-Salzler M and Moldawer LL: Apoptosis in sepsis: A new target for therapeutic exploration. FASEB J. 15:879–892. 2001.PubMed/NCBI View Article : Google Scholar
36	Tinsley KW, Cheng SL, Buchman TG, Chang KC, Hui JJ, Swanson PE, Karl IE and Hotchkiss RS: Caspases -2, -3, -6, and -9, but not caspase-1, are activated in sepsis-induced thymocyte apoptosis. Shock. 13:1–7. 2000.
37	Weber P, Wang P, Maddens S, Wang PSh, Wu R, Miksa M, Dong W, Mortimore M, Golec JM and Charlton P: VX-166: A novel potent small molecule caspase inhibitor as a potential therapy for sepsis. Crit Care. 13(R146)2009.PubMed/NCBI View Article : Google Scholar
38	Gagnon JD, Kageyama R, Shehata HM, Fassett MS, Mar DJ, Wigton EJ, Johansson K, Litterman AJ, Odorizzi P, Simeonov D, et al: MiR-15/16 restrain memory T cell differentiation, cell cycle, and survival. Cell Rep. 28:2169–2181.e4. 2019.PubMed/NCBI View Article : Google Scholar
39	Li B, Wang X, Choi IY, Wang YC, Liu S, Pham AT, Moon H, Smith DJ, Rao DS, Boldin MP and Yang L: MiR-146a modulates autoreactive Th17 cell differentiation and regulates organ-specific autoimmunity. J Clin Invest. 127:3702–3716. 2017.PubMed/NCBI View Article : Google Scholar
40	Agudo J, Ruzo A, Tung N, Salmon H, Leboeuf M, Hashimoto D, Becker C, Garrett-Sinha LA, Baccarini A, Merad M and Brown BD: The miR-126-VEGFR2 axis controls the innate response to pathogen-associated nucleic acids. Nat Immunol. 15:54–62. 2014.PubMed/NCBI View Article : Google Scholar
41	Qin A, Wen Z, Zhou Y, Li Y, Li Y, Luo J, Ren T and Xu L: MicroRNA-126 regulates the induction and function of CD4(+) Foxp3(+) regulatory T cells through PI3K/AKT pathway. J Cell Mol Med. 17:252–264. 2013.PubMed/NCBI View Article : Google Scholar
42	Han L, Liu H, Wu J and Liu J: MiR-126 suppresses invasion and migration of malignant glioma by targeting mature T cell proliferation 1 (MTCP1). Med Sci Monit. 24:6630–6637. 2018.PubMed/NCBI View Article : Google Scholar
43	Zhao S, Wang Y, Liang Y, Zhao M, Long H, Ding S, Yin H and Lu Q: MicroRNA-126 regulates DNA methylation in CD4⁺ T cells and contributes to systemic lupus erythematosus by targeting DNA methyltransferase 1. Arthritis Rheum. 63:1376–1386. 2011.PubMed/NCBI View Article : Google Scholar
44	Yang G, Wu D, Zeng G, Jiang O, Yuan P, Huang S, Zhu J, Tian J, Weng Y and Rao Z: Correlation between miR-126 expression and DNA hypomethylation of CD4⁺ T cells in rheumatoid arthritis patients. Int J Clin Exp Pathol. 8:8929–8936. 2015.PubMed/NCBIeCollection, 2015.
45	Tian M, Ji Y, Wang T, Zhang W, Zhou Y and Cui Y: Changes in circulating microRNA-126 levels are associated with immune imbalance in children with acute asthma. Int J Immunopathol Pharmacol. 32(2058738418779243)2018.PubMed/NCBI View Article : Google Scholar
46	Hotchkiss RS, Tinsley KW, Swanson PE, Schmieg RE Jr, Hui JJ, Chang KC, Osborne DF, Freeman BD, Cobb JP, Buchman TG and Karl IE: Sepsis-induced apoptosis causes progressive profound depletion of B and CD4⁺ T lymphocytes in humans. J Immunol. 166:6952–6963. 2001.PubMed/NCBI View Article : Google Scholar
47	Jones Buie JN, Zhou Y, Goodwin AJ, Cook JA, Vournakis J, Demcheva M, Broome AM, Dixit S, Halushka PV and Fan H: Application of deacetylated poly-N-acetyl glucosamine nanoparticles for the delivery of miR-126 for the treatment of cecal ligation and puncture-induced sepsis. Inflammation. 42:170–184. 2019.PubMed/NCBI View Article : Google Scholar
48	Su J and Ding L: Upregulation of miR-126 inhibits podocyte injury in sepsis via EGFL6/DKC1 signaling pathway. Mol Med Rep. 23(373)2021.PubMed/NCBI View Article : Google Scholar
49	Smigielska-Czepiel K, van den Berg A, Jellema P, Slezak-Prochazka I, Maat H, van den Bos H, van der Lei RJ, Kluiver J, Brouwer E, Boots AM and Kroesen BJ: Dual role of miR-21 in CD4⁺ T-cells: Activation-induced miR-21 supports survival of memory T-cells and regulates CCR7 expression in naive T-cells. PLoS One. 8(e76217)2013.PubMed/NCBI View Article : Google Scholar