Correlation of the expression of YY1 and Fas cell surface death receptor with apoptosis of peripheral blood mononuclear cells, and the development of multiple organ dysfunction in children with sepsis

Reséndiz‑Martínez,Judith; Asbun‑Bojalil,Juan; Huerta‑Yepez,Sara; Vega,Mario

doi:10.3892/mmr.2017.6310

Correlation of the expression of YY1 and Fas cell surface death receptor with apoptosis of peripheral blood mononuclear cells, and the development of multiple organ dysfunction in children with sepsis

Authors:
- Judith Reséndiz‑Martínez
- Juan Asbun‑Bojalil
- Sara Huerta‑Yepez
- Mario Vega
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Affiliations: Servicio de Terapia Intensiva Pediátrica, Hospital General Dr Gaudencio González Garza, Centro Medico La Raza IMSS, 02990 Mexico City, Mexico, Unidad de Investigación en Enfermedades Oncológicas, Hospital Infantil de México Federico Gómez S.S.A, 06720 Mexico City, Mexico, Oncology Research Unit, Oncology Hospital, Siglo XXI National Medical Center, IMSS, 06720 Mexico City, Mexico
Published online on: March 9, 2017 https://doi.org/10.3892/mmr.2017.6310
Pages: 2433-2442
Copyright: © Reséndiz‑Martínez et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Multiple organ dysfunction (MOD) is a lethal complication in children with sepsis. Apoptosis of several cell types is involved in this process, and it is associated with increased Fas cell surface death receptor (Fas) expression. As YY1 transcription factor (YY1) negatively regulates the expression of Fas in cancer models, and is associated with the clinical outcome, it may be important in MOD. The present study aimed to determine the association between the expression of Fas, YY1 and apoptosis in children with sepsis, and its association with MOD, these factors were analyzed in 30 pediatric patients that had been diagnosed with sepsis. Peripheral blood mononuclear cells were purified from patients, and YY1 and Fas protein expression was assessed by immunocytochemistry. Apoptosis was determined by terminal deoxynucleotidyl transferase dUTP nick‑end labeling. Sepsis was monitored using clinical parameters, pediatric logistic organ dysfunction (PELOD) score and the pediatric mortality index. The results demonstrated that Fas expression was directly correlated with apoptosis levels and the expression of YY1 was inversely correlated with apoptosis levels. Patients with high levels of apoptosis exhibited increased disease severity and poor clinical outcome. Notably, the findings of the present study demonstrated that there were higher survival rates in patients with high YY1 expression, compared with those with low YY1 expression. Additionally, patients with MOD exhibited lower proportions of apoptotic cells compared with sepsis patients without MOD. Furthermore, the PELOD score was positively correlated with Fas and inversely correlated with YY1 expression. Finally, high apoptosis and low YY1 expression were prognostic factors associated with poor survival rates. These data suggested that YY1 may be important for apoptosis induction via the regulation of Fas during sepsis. Therefore, Fas may be a potential therapeutic target to prevent MOD through regulation of YY1 expression. Furthermore, YY1 and Fas expression in PBMCs may be used to as prognostic markers.

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1	Hotchkiss RS and Nicholson DW: Apoptosis and caspases regulate death and inflammation in sepsis. Nat Rev Immunol. 6:813–822. 2006. View Article : Google Scholar : PubMed/NCBI
2	Rayo AC, Hernández GL, Huerta GL, Ortiz AV, Reyes RM and Gómez RG: Mecanismos patogénicos en sepsis y choque séptico. Med Interna Mex. 24:38–42. 2008.
3	Carrillo-Esper R, Carrillo-Cordova JR and Carrillo-Cordova LD: Epidemiological study of sepsis in Mexican intensive care units. Cir Cir. 77:279–385. 2009.(In Spanish). PubMed/NCBI
4	Hotchkiss RS, Swanson PE, Freeman BD, Tinsley KW, Cobb JP, Matuschak GM, Buchman TG and Karl IE: Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction. Crit Care Med. 27:1230–1251. 1999. View Article : Google Scholar : PubMed/NCBI
5	Hotchkiss RS, Swanson PE, Cobb JP, Jacobson A, Buchman TG and Karl IE: Apoptosis in lymphoid and parenchymal cells during sepsis: Findings in normal and T- and B-cell-deficient mice. Crit Care Med. 25:1298–1307. 1997. View Article : Google Scholar : PubMed/NCBI
6	Hotchkiss RS, Swanson PE, Knudson CM, Chang KC, Cobb JP, Osborne DF, Zollner KM, Buchman TG, Korsmeyer SJ and Karl IE: Overexpression of Bcl-2 in transgenic mice decreases apoptosis and improves survival in sepsis. J Immunol. 162:4148–4156. 1999.PubMed/NCBI
7	Chung CS, Song GY, Moldawer LL, Chaudry IH and Ayala A: Neither fas ligand nor endotoxin is responsible for inducible peritoneal phagocyte apoptosis during sepsis/peritonitis. J Surg Res. 91:147–153. 2000. View Article : Google Scholar : PubMed/NCBI
8	Hotchkiss RS, Osmon SB, Chang KC, Wagner TH, Coopersmith CM and Karl IE: Accelerated lymphocyte death in sepsis occurs by both the death receptor and mitochondrial pathways. J Immunol. 174:5110–5118. 2005. View Article : Google Scholar : PubMed/NCBI
9	Niu J, Azfer A and Kolattukudy PE: Protection against lipopolysaccharide-induced myocardial dysfunction in mice by cardiac-specific expression of soluble Fas. J Mol Cell Cardiol. 44:160–169. 2008. View Article : Google Scholar : PubMed/NCBI
10	Ren Y, Xie Y, Jiang G, Fan J, Yeung J, Li W, Tam PK and Savill J: Apoptotic cells protect mice against lipopolysaccharide-induced shock. J Immunol. 180:4978–4985. 2008. View Article : Google Scholar : PubMed/NCBI
11	Gautier EL, Huby T, Saint-Charles F, Ouzilleau B, Chapman MJ and Lesnik P: Enhanced dendritic cell survival attenuates lipopolysaccharide-induced immunosuppression and increases resistance to lethal endotoxic shock. J Immunol. 180:6941–6946. 2008. View Article : Google Scholar : PubMed/NCBI
12	Unsinger J, Herndon JM, Davis CG, Muenzer JT, Hotchkiss RS and Ferguson TA: The role of TCR engagement and activation-induced cell death in sepsis-induced T cell apoptosis. J Immunol. 177:7968–7973. 2006. View Article : Google Scholar : PubMed/NCBI
13	Ayala A, Urbanich MA, Herdon CD and Chaudry IH: Is sepsis-induced apoptosis associated with macrophage dysfunction? J Trauma. 40:568–574. 1996. View Article : Google Scholar : PubMed/NCBI
14	Sharshar T, Gray F, Poron F, Raphael JC, Gajdos P and Annane D: Multifocal necrotizing leukoencephalopathy in septic shock. Crit Care Med. 30:2371–2375. 2002. View Article : Google Scholar : PubMed/NCBI
15	Gordon S, Akopyan G, Garban H and Bonavida B: Transcription factor YY1: Structure, function, and therapeutic implications in cancer biology. Oncogene. 25:1125–1142. 2006. View Article : Google Scholar : PubMed/NCBI
16	Huerta-Yepez S, Vega M, Garban H and Bonavida B: Involvement of the TNF-alpha autocrine-paracrine loop, via NF-kappaB and YY1, in the regulation of tumor cell resistance to Fas-induced apoptosis. Clin Immunol. 120:297–309. 2006. View Article : Google Scholar : PubMed/NCBI
17	Garbán HJ and Bonavida B: Nitric oxide inhibits the transcription repressor Yin-Yang 1 binding activity at the silencer region of the Fas promoter: A pivotal role for nitric oxide in the up-regulation of Fas gene expression in human tumor cells. J Immunol. 167:75–81. 2001. View Article : Google Scholar : PubMed/NCBI
18	De Freitas I, Fernández-Somoza M, Essenfeld-Sekler E and Cardier JE: Serum levels of the apoptosis-associated molecules, tumor necrosis factor-alpha/tumor necrosis factor type-I receptor and Fas/FasL, in sepsis. Chest. 125:2238–2246. 2004. View Article : Google Scholar : PubMed/NCBI
19	Hotchkiss RS, Tinsley KW and Karl IE: Role of apoptotic cell death in sepsis. Scand J Infect Dis. 35:585–592. 2003. View Article : Google Scholar : PubMed/NCBI
20	Adrie C, Bachelet M, Vayssier-Taussat M, Russo-Marie F, Bouchaert I, Adib-Conquy M, Cavaillon JM, Pinsky MR, Dhainaut JF and Polla BS: Mitochondrial membrane potential and apoptosis peripheral blood monocytes in severe human sepsis. Am J Respir Crit Care Med. 164:389–395. 2001. View Article : Google Scholar : PubMed/NCBI
21	World Medical Association: World Medical Association Declaration of Helsinki: Ethical principles for medical research involving human subjects. JAMA. 310:2191–2194. 2013. View Article : Google Scholar : PubMed/NCBI
22	Holmström TH and Eriksson JE: Phosphorylation-based signaling in Fas receptor-mediated apoptosis. Crit Rev Immunol. 20:121–152. 2000. View Article : Google Scholar : PubMed/NCBI
23	Rathmell JC and Thompson CB: Pathways of apoptosis in lymphocyte development, homeostasis, and disease. Cell. 109:(Suppl). S97–S107. 2002. View Article : Google Scholar : PubMed/NCBI
24	Fadeel B and Orrenius S: Apoptosis: A basic biological phenomenon with wide-ranging implications in human disease. J Intern Med. 258:479–517. 2005. View Article : Google Scholar : PubMed/NCBI
25	Wyllie AH, Morris RG, Smith AL and Dunlop D: Chromatin cleavage in apoptosis: Association with condensed chromatin morphology and dependence on macromolecular synthesis. J Pathol. 142:67–77. 1984. View Article : Google Scholar : PubMed/NCBI
26	Porter BO and Malek TR: Prostaglandin E2 inhibits T cell activation-induced apoptosis and Fas-mediated cellular cytotoxicity by blockade of Fas-ligand induction. Eur J Immunol. 29:2360–2365. 1999. View Article : Google Scholar : PubMed/NCBI
27	McCarthy NJ, Smith CA and Williams GT: Apoptosis in the development of the immune system: Growth factors, clonal selection and bcl-2. Cancer Metastasis Rev. 11:157–178. 1992. View Article : Google Scholar : PubMed/NCBI
28	Newton K and Strasser A: Cell death control in lymphocytes. Adv Immunol. 76:179–226. 2000. View Article : Google Scholar : PubMed/NCBI
29	Toledano BJ, Bastien Y, Noya F and Mazer B: Characterization of B lymphocytes rescued from apoptosis by platelet-activating factor. Cell Immunol. 191:60–68. 1999. View Article : Google Scholar : PubMed/NCBI
30	Ashare A, Monick MM, Powers LS, Yarovinsky T and Hunninghake GW: Severe bacteremia results in a loss of hepatic bacterial clearance. Am J Respir Crit Care Med. 173:644–652. 2006. View Article : Google Scholar : PubMed/NCBI
31	Stearns-Kurosawa DJ, Osuchowski MF, Valentine C, Kurosawa S and Remick DG: The pathogenesis of sepsis. Annu Rev Pathol. 6:19–48. 2011. View Article : Google Scholar : PubMed/NCBI
32	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. View Article : Google Scholar : PubMed/NCBI
33	Hotchkiss RS, Chang KC, Swanson PE, Tinsley KW, Hui JJ, Klender P, Xanthoudakis S, Roy S, Black C, Grimm E, et al: Caspase inhibitors improve survival in sepsis: A critical role of the lymphocyte. Nat Immunol. 1:496–501. 2000. View Article : Google Scholar : PubMed/NCBI
34	Roth E and Pircher H: IFN-gamma promotes Fas ligand- and perforin-mediated liver cell destruction by cytotoxic CD8 T cells. J Immunol. 172:1588–1594. 2004. View Article : Google Scholar : PubMed/NCBI
35	Doughty L, Clark RS, Kaplan SS, Sasser H and Carcillo J: sFas and sFas ligand and pediatric sepsis-induced multiple organ failure syndrome. Pediatr Res. 52:922–927. 2002. View Article : Google Scholar : PubMed/NCBI
36	Vega MI, Jazirehi AR, Huerta-Yepez S and Bonavida B: Rituximab-induced inhibition of YY1 and Bcl-xL expression in Ramos non-Hodgkin's lymphoma cell line via inhibition of NF-kappa B activity: Role of YY1 and Bcl-xL in Fas resistance and chemoresistance, respectively. J Immunol. 175:2174–2183. 2005. View Article : Google Scholar : PubMed/NCBI
37	Krippner-Heidenreich A, Walsemann G, Beyrouthy MJ, Speckgens S, Kraft R, Thole H, Talanian RV, Hurt MM and Lüscher B: Caspase-dependent regulation and subcellular redistribution of the transcriptional modulator YY1 during apoptosis. Mol Cell Biol. 25:3704–3714. 2005. View Article : Google Scholar : PubMed/NCBI
38	Guo J, Casolaro V, Seto E, Yang WM, Chang C, Seminario MC, Keen J and Georas SN: Yin-Yang 1 Activates Interleukin-4 Gene Expression in T Cells. J Biol Chem. 276:48871–48878. 2001. View Article : Google Scholar : PubMed/NCBI
39	Denlinger LC and Proctor RA: Potential risk factors for developing apoptosis during septic shock. Crit Care Med. 28:2133–2134. 2000. View Article : Google Scholar : PubMed/NCBI
40	Sakhinia E, Glennie C, Hoyland JA, Menasce LP, Brady G, Miller C, Radford JA and Byers RJ: Clinical quantitation of diagnostic and predictive gene expression levels in follicular and diffuse large B-cell lymphoma by RT-PCR gene expression profiling. Blood. 109:3922–3928. 2007. View Article : Google Scholar : PubMed/NCBI
41	Krammer PH: CD95(APO-1/Fas)-mediated apoptosis: Live and let die. Adv Immunol. 71:163–210. 1999. View Article : Google Scholar : PubMed/NCBI
42	Hofer S, Brenner T, Bopp C, Steppan J, Lichtenstern C, Weitz J, Bruckner T, Martin E, Hoffmann U and Weigand MA: Cell death serum biomarkers are early predictors for survival in severe septic patients with hepatic dysfunction. Crit Care. 13:R932009. View Article : Google Scholar : PubMed/NCBI
43	Leteurtre S, Martinot A, Duhamel A, Proulx F, Grandbastien B, Cotting J, Gottesman R, Joffe A, Pfenninger J, Hubert P, et al: Validation of the paediatric logistic organ dysfunction (PELOD) score: Prospective, observational, multicentre study. Lancet. 362:192–197. 2003. View Article : Google Scholar : PubMed/NCBI
44	Proulx F, Gauthier M, Nadeau D, Lacroix J and Farrell CA: Timing and predictors of death in pediatric patients with multiple organ system failure. Crit Care Med. 22:1025–1031. 1994. View Article : Google Scholar : PubMed/NCBI