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Critical Care
Published in: Critical Care 3/2011

Open Access 01-06-2011 | Research

Post-operative infection and sepsis in humans is associated with deficient gene expression of γccytokines and their apoptosis mediators

Authors: Mary White, Vivienne Mahon, Robert Grealy, Derek G Doherty, Patrick Stordeur, Dermot P Kelleher, Ross McManus, Thomas Ryan

Published in: Critical Care | Issue 3/2011

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Abstract

Introduction

Lymphocyte homeostasis is dependent on the γc cytokines. We hypothesised that sepsis in humans is associated with differential gene expression of the γc cytokines and their associated apoptosis mediators.

Methods

The study population consisted of a total of 60 patients with severe sepsis, 15 with gram negative bacteraemia, 10 healthy controls and 60 patients undergoing elective lung resection surgery. Pneumonia was diagnosed by CDC NNIC criteria. Gene expression in peripheral blood leukocytes (PBLs) of interleukin (IL)-2, 7, 15 and interferon (IFN)-γ, Bax, Bim, Bcl-2 was determined by qRT-PCR and IL-2 and IL-7 serum protein levels by ELISA. Gene expression of IL-2, 7 and IFN-γ was measured in peripheral blood leukocytes (PBL), cultured in the presence of lipopolysacharide (LPS) and CD3 binding antibody (CD3ab)

Results

IL-2 gene expression was lower in the bacteraemia group compared with controls, and lower still in the sepsis group (P < 0.0001). IL-7 gene expression was similar in controls and bacteraemia, but lower in sepsis (P < 0.0001). IL-15 gene expression was similar in the three groups. Bcl-2 gene expression was less (P < 0.0001) and Bim gene expression was greater (P = 0.0003) in severe sepsis compared to bacteraemic and healthy controls. Bax gene expression was similar in the three groups.
In lung resection surgery patients, post-operative pneumonia was associated with a perioperative decrease in IL-2 mRNA (P < 0.0001) and IL-7 mRNA (P = 0.003). IL-2 protein levels were reduced in sepsis and bacteraemia compared to controls (P = 0.02) but similar in pneumonia and non-pneumonia groups. IL-7 protein levels were similar in all groups.
In cultured PBLs, IFN-γ gene expression was decreased in response to LPS and increased in response to CD3ab with sepsis: IL-7 gene expression increased in response to LPS in controls and to CD3ab with sepsis; Bcl-2 gene expression decreased in response to combined CD3ab and IL-2 with sepsis.

Conclusions

Patients with infection and sepsis have deficient IL-2 and IL-7 gene expression in PBLs. Aberrant cytokine gene expression may precede the onset of infection.
Appendix
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Literature
1.
Schluns KS, Lefrancois L: Cytokine control of memory T-cell development and survival. Nat Rev Immunol. 2003, 3: 269-279. 10.1038/nri1052.CrossRefPubMed
2.
Fry TJ, Mackall CL: The many faces of IL-7: From lymphopoeisis to peripheral T cell maintenance. J Immunol. 2005, 174: 6571-6576.CrossRefPubMed
3.
Ma A, Koka R, Burkett P: Diverse functions of IL-2, IL-15, and IL-7 in lymphoid homeostasis. Annu Rev Immunol. 2006, 24: 657-679. 10.1146/annurev.immunol.24.021605.090727.CrossRefPubMed
4.
Khaled AR, Durum SK: Lymphocide:cytokines and the control of lymphoid homeostasis. Nat Rev Immunol. 2002, 2: 817-830. 10.1038/nri931.CrossRefPubMed
5.
Lord JD, McIntosh BC, Greenberg PD, Nelson BH: The IL-2 receptor promotes lymphocyte proliferation and induction of the c-myc, bcl-2 and the bcl-x gene through the activation domain of Stat5. J Immunol. 2000, 164: 2533-2541.CrossRefPubMed
6.
Duggan E, Caraher E, Gately K, O'Dwyer M, McGovern E, Kelleher D, McManus R, Ryan T: Tumor necrosis factor-alpha and interleukin-10 gene expression in peripheral blood mononuclear cells after cardiac surgery. Crit Care Med. 2006, 34: 2134-2139. 10.1097/01.CCM.0000227647.77356.AB.CrossRefPubMed
7.
O'Dwyer MJ, Mankan AK, Stordeur P, O'Connell B, Duggan E, White M, Kelleher DP, McManus R, Ryan T: The occurrence of severe sepsis and septic shock are related to distinct patterns of cytokine gene expression. Shock. 2006, 26: 544-550. 10.1097/01.shk.0000235091.38174.8d.CrossRefPubMed
8.
O'Dwyer MJ, Mankan AK, White M, Lawless MW, Stordeur P, O'Connell B, Kelleher DP, McManus R, Ryan R: The human host response to infection is associated with distinct patterns of interleukin 23 and interleukin 27 expression. Intensive Care Med. 2008, 34: 683-691. 10.1007/s00134-007-0968-5.CrossRefPubMed
9.
White M, Lawless MW, O'Dwyer MJ, Greally R, O'Connell B, Stordeur P, Kelleher D, McManus R, Ryan T: Transforming growth factor beta- 1 and interleukin - 17 gene transcription in peripheral blood mononuclear cells and the human host response to infection. Cytokine. 2010, 50: 322-327. 10.1016/j.cyto.2010.01.003.CrossRefPubMed
10.
White M, Martin-Loeches I, Lawless MW, O'Dwyer MJ, Doherty DG, Young V, Kelleher D, McManus R, Ryan T: Hospital acquired pneumonia after lung resection surgery is associated with characteristic gene expression. Chest. 2011, 139: 626-632. 10.1378/chest.10-0016.CrossRefPubMed
11.
Stordeur P, Poulin LF, Craciun L, Zhou L, Schandene L, de Lavareille A, Goriely S, Goldman M: Cytokine mRNA quantification by real-time PCR. J Immunol Methods. 2002, 259: 55-64. 10.1016/S0022-1759(01)00489-6. Erratum in: J Immunol Methods 2002, 262:229CrossRefPubMed
12.
Unsinger J, Kazama H, McDonough JS, Griffith TS, Hotchkiss RS, Ferguson TA: Sepsis-induced apoptosis leads to active suppression of delayed-type hypersensitivity by CD8+ regulatory T cells through a TRAIL-dependent mechanism. J Immunol. 2010, 15184: 6766-6772.CrossRef
13.
Unsinger J, McDonough JS, Shultz LD, Ferguson TA, Hotchkiss RS: Sepsis-induced human lymphocyte apoptosis and cytokine production in "humanized" mice. J Leukoc Biol. 2009, 86: 219-227. 10.1189/jlb.1008615.PubMedCentralCrossRefPubMed
14.
Hoogerwerf JJ, van Zoelen MA, Wiersinga WJ, van 't Veer C, de Vos AF, de Boer A, Schultz MJ, Hooibrink B, de Jonge E, van der Poll T: Gene expression profiling of apoptosis regulators in patients with sepsis. J Innate Immun. 2010, 2: 461-468. 10.1159/000317035.CrossRefPubMed
15.
Schussler O, Allfano M, Dermine H, Strano S, Casetta A, Sepulveda S, Chaflk A, Colgnard S, Rabbat A, Regnard JF: Postoperative pneumonia after major lung resection. Am J Respir Crit Care Med. 2006, 173: 1161-1169. 10.1164/rccm.200510-1556OC.CrossRefPubMed
16.
American College of Chest Physicians, Society of Critical Care Medicine Consensus Conference: Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med. 1992, 20: 864-874. 10.1097/00003246-199206000-00025.CrossRef
17.
Le Gall JR, Lemeshow S, Saulnier F: A new simplified Acute Physiology Score (SAPS II) based on a European/North American multicentre study. JAMA. 1993, 270: 2957-2963. 10.1001/jama.270.24.2957.CrossRefPubMed
18.
Vincent JL, Moreno R, Takala J, Willatts S, De Mendonca A, Bruining H, Reinhart CK, Suter PM, Thijs LG: The SOFA (Sepsis-related Organ failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of theEuropean Society of Intensive Care Medicine. Intensive Care Med. 1996, 22: 707-710. 10.1007/BF01709751.CrossRefPubMed
19.
Centers for Disease Control and Prevention: CDC definitions of nosocomial infections. Am RevRespir Dis. 1989, 139: 1058-1059.CrossRef
20.
Sojka DK, Bruniquel D, Schwartz RH, Singh NJ: IL-2 secretion by CD4+ T cells in vivo is rapid, transient, and influenced by TCR-specific competition. J Immunol. 2004, 172: 6136-6143.CrossRefPubMed
21.
Kim HP, Imbert J, Leonard W: Both integrated and differential regulation of components of the IL2/IL-2 receptor system. Cytokine Growth Factor Rev. 2006, 17: 349-366. 10.1016/j.cytogfr.2006.07.003.CrossRefPubMed
22.
Liao W, Schones DE, Oh J, Cui Y, Cui K, Roh TY, Zhao K, Leonard W: Priming for T helper type 2 differentiation by interleukin 2-mediated induction of interleukin 4 receptor alpha chain expression. Nat Immun. 2008, 9: 1288-1296. 10.1038/ni.1656.CrossRef
23.
Sakaguchi S: Regulatory T cells: key controllers of immunologic self-tolerance. Cell. 2000, 101: 455-458. 10.1016/S0092-8674(00)80856-9.CrossRefPubMed
24.
Setoguchi R, Hori S, Takahashi T, Sakaguchi S: Homeostatic maintenance of natural Foxp3+CD25+CD4+ regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralisation. JEM. 2005, 201: 723-735. 10.1084/jem.20041982.CrossRef
25.
Kinter A, Godbout E, McNally JP, Sereti I, Roby G, O'Shea MA, Fauci A: The common gamma-chain cytokines IL-2, IL-7, IL-15, and IL-21 induce the expression of programmed Death-1 and its ligands. J Immunol. 2008, 181: 6738-6746.CrossRefPubMed
26.
Muenzer JT, Davis CG, Chang K, Schmidt RE, Dunne WM, Coopersmith CM, Hotchkiss RS: Characterization and modulation of the immunosuppressive phase of sepsis. Infect Immun. 2010, 78: 1582-1592. 10.1128/IAI.01213-09.PubMedCentralCrossRefPubMed
27.
Wesche DE, Lomas-Neira JL, Perl M, Chung CS, Ayala A: Leukocyte apoptosis and its significance in sepsis and shock. J Leukoc Biol. 2005, 78: 325-337. 10.1189/jlb.0105017.CrossRefPubMed
28.
Unsinger J, McGlynn M, Kasten KR, Hoekzema AS, Watanabe E, Muenzer JT, McDonagh JS, Tschoep J, Ferguson TA, McDunn JE, Morre M, Hildeman DA, Caldwell CC, Hotchkiss RS: IL-7 promotes T cell viability, trafficking, and functionality and improves survival in sepsis. J Immunol. 2010, 184: 3768-3779. 10.4049/jimmunol.0903151.PubMedCentralCrossRefPubMed
29.
Guimond M, Veenstra RG, Grindler DJ, Zhang H, Cui Y, Murphy RD, Kim SY, Na R, Hennighausen L, Kurtulus S, Erman B, Matzinger P, Merchant MS, Mackall CL: Interleukin 7 signaling in dendritic cells regulates the homeostatic proliferation and niche size of CD4+ T cells. Nat Immunol. 2009, 10: 149-157.PubMedCentralCrossRefPubMed
30.
Saini M, Pearson C, Seddon B: Regulation of T cell-dendritic cell interactions by IL-7 governs T-cell activation and homeostasis. Blood. 2009, 113: 5793-5800. 10.1182/blood-2008-12-192252.PubMedCentralCrossRefPubMed
31.
Napolitano LA, Grant RM, Deeks SG, Schmidt D, De Rosa SC, Herzenberg LA, Herndier BG, Andersson J, McCune JM: Increased production of IL-7 accompanies HIV-1-mediated T-cell depletion:implications for T cell homeostasis. Nat Med. 2001, 7: 73-79. 10.1038/83381.CrossRefPubMed
32.
Vranjkovic A, Crawley AM, Gee K, Kumar A, Angel JB: IL-7 decreases IL-7 receptor alpha (CD127) expression by human CD8+ T cells. Int Immunol. 2007, 19: 1329-1339. 10.1093/intimm/dxm102.CrossRefPubMed
33.
Mazzucchelli R, Durum SK: Interleukin-7 receptor expression: intelligent design. Nat Rev Immunol. 2007, 7: 144-154. 10.1038/nri2023.CrossRefPubMed
34.
Pellegrini M, Bouillet P, Robati M, Belz GT, Davey GM, Strasser A: Loss of Bim increases T cell production and function in interleukin 7 receptor-deficient mice. J Exp Med. 2004, 200: 1189-1195. 10.1084/jem.20041328.PubMedCentralCrossRefPubMed
35.
Schluns KS, Kieper WC, Jameson SC, Lefrancois L: Interleukin-7 mediates the homeostasis of naive and memory CD8 T cells in vivo. Nat Immunol. 2000, 1: 426-432. 10.1038/80868.CrossRefPubMed
36.
Spolski R, Kashyap M, Robinson C, Yu Z, Leonard WJ: IL-21 signalling is critical for the development of type I diabetes in the NOD mouse. Proc Natl Acad Sci USA. 2008, 105: 14028-14033. 10.1073/pnas.0804358105.PubMedCentralCrossRefPubMed
37.
Datta S, Sarvetnick NE: IL-21 limits peripheral lymphocyte numbers through T cell homeostatic mechanisms. PLoS ONE. 2008, 3: e3118-10.1371/journal.pone.0003118.PubMedCentralCrossRefPubMed
38.
Boehm U, Klamp T, Groot M, Howard JC: Cellular responses to interferon-gamma. Annu Rev Immunol. 1997, 15: 749-795. 10.1146/annurev.immunol.15.1.749.CrossRefPubMed
39.
Deng JC, Zeng X, Newstead M, Moore TA, Tsai WC, Thannickal VJ, Standiford TJ: STAT4 is a critical mediator of early innate immune responses against pulmonary Klebsiella infection. J Immunol. 2004, 173: 4075-4083.PubMedCentralCrossRefPubMed
40.
Turrel-Davin F, Guignant C, Lepape A, Mougin B, Monneret G, Venet F: Upregulation of the pro-apoptotic genes BID and FAS in septic shock patients. Crit Care. 2010, 14: R133-10.1186/cc9181.PubMedCentralCrossRefPubMed
41.
Weber S, Schewe J, Lehman L, Muller S, Book M, Klaschik S, Hoeft A, Stuber F: Induction of Bim and Bid gene expression during accelerated apoptosis in severe sepsis. Crit Care. 2008, 12: R128-10.1186/cc7088.PubMedCentralCrossRefPubMed
42.
Bilbault P, Lavaux T, Lahlou A, Uring-Lambert B, Gaub M P, Ratomponirina C, Meyer N, Oudet P, Schnelder F: Transient Bcl-2 gene down-expression in circulating mononuclear cells of severe sepsis patients who died despite appropriate intensive care. Intensive Care Med. 2004, 30: 408-415. 10.1007/s00134-003-2118-z.CrossRefPubMed
43.
Rochman Y, Spolski R, Leonard WJ: New insights into the regulation of T cells by γc family cytokines. Nat Rev Immunol. 2009, 9: 480-503. 10.1038/nri2580.PubMedCentralCrossRefPubMed
44.
Dimopoulou I, Orfanos S, Kotanidou A, Livaditi O, Giamarellos-Bourboulis E, Athanasiou C, Korovesi I, Sotiropoulou C, Kopterides P, Ilias I, Kanellakopoulou K, Armaganidis A: Plasma pro- and anti-inflammatory cytokine levels and outcome prediction in unselected critically ill patients. Cytokine. 2008, 41: 263-267. 10.1016/j.cyto.2007.11.019.CrossRefPubMed
45.
Lukaszewicz AC, Greinay M, Resche-Rigon M, Pirracchio R, Faivre V, Boval B, Payen D: Monocyte HLA-DR expression in intensive care patients: interest for prognosis and secondary infection prediction. Crit Care Med. 2009, 37: 2746-2752. 10.1097/CCM.0b013e3181ab858a.CrossRefPubMed
Metadata
Title
Post-operative infection and sepsis in humans is associated with deficient gene expression of γccytokines and their apoptosis mediators
Authors
Mary White
Vivienne Mahon
Robert Grealy
Derek G Doherty
Patrick Stordeur
Dermot P Kelleher
Ross McManus
Thomas Ryan
Publication date
01-06-2011
Publisher
BioMed Central
Published in
Critical Care / Issue 3/2011
Electronic ISSN: 1364-8535
DOI
https://doi.org/10.1186/cc10293

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