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TNF-α, IL-6, and IL-8 Cytokines and Their Association with TNF-α-308 G/A Polymorphism and Postoperative Sepsis

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Journal of Gastrointestinal Surgery Aims and scope

Abstract

Introduction

Early prediction of postoperative sepsis remains an enormous clinical challenge. Association of TNF-α-308 G/A polymorphism with sepsis remains controversial. We, therefore, investigated this polymorphism with serum levels of cytokines TNF-α, IL-6, and IL-8 in relation to development of sepsis following major gastrointestinal surgery.

Methods

Two hundred and thirty-nine patients undergoing major gastrointestinal surgery were enrolled. Polymorphism was studied through the analysis of restriction fragments of Nco1-digested DNA with the polymerase chain reaction. All patients were followed for 1 month following surgery for evidence of sepsis. Levels of serum cytokines TNF-α, IL-6, and IL-8 were measured preoperatively and postoperatively by enzyme-linked immunosorbent assay (ELISA).

Results

Forty-seven (19.66 %) patients developed postoperative sepsis. Patients with postoperative sepsis were significantly (p = 0.002) more likely to possess AA homozygous genotype with higher capacity to produce cytokines TNF-α (p < 0.0001), IL-6 (p < 0.0001), and IL-8 (p < 0.0001) as compared to other genotypes. When compared with patients carrying at least one G allele, the AA genotype was associated with a significantly higher probability (odds ratio (OR) = 4.17; p = 0.003; 95 % confidence interval (CI) = 1.5–11.48) of developing sepsis. Compared with the GG genotype, AA was associated with a significantly higher probability (OR = 5.18; p = 0.0008; 95 % CI = 1.82–14.76) of sepsis development.

Conclusion

TNF-α-308 G/A polymorphism is significantly associated with the development of postoperative sepsis and with increased expression of cytokines TNF-α, IL-6, and IL-8.

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References

  1. Faist E, Wichmann M, Kim C: Immunosuppression and immunomodulation in surgical patients. Curr Opin Crit Care 1997;3:293-298.

    Article  Google Scholar 

  2. Beutler B, Grau GE: Tumor Necrosis Factor in the pathogenesis of infectious diseases. Crit Care Med 1993;21:S423-435.

    Article  CAS  PubMed  Google Scholar 

  3. Bazzoni F, Beutler B: The Tumor Necrosis Factor ligand and receptor families. N Engl J Med 1996;334:1717-1725.

    Article  CAS  PubMed  Google Scholar 

  4. Wheeler AP, Bernard GR: Treating patients with severe sepsis. N Engl J Med 1999;340:207-214.

    Article  CAS  PubMed  Google Scholar 

  5. Debets JM, Kampmeijer R, van der Linden MP, Buurman WA, van der Linden CJ: Plasma Tumor Necrosis Factor and mortality in critically ill septic patients. Crit Care Med 1989;17:489-494.

    Article  CAS  PubMed  Google Scholar 

  6. Westendorp RG, Langermans JA, Huizinga TW, Elouali AH, Verweij CL, Boomsma DI, Vandenbroucke JP: Genetic influence on cytokine production and fatal meningococcal disease. Lancet 1997;349:170-173.

    Article  CAS  PubMed  Google Scholar 

  7. Rink L, Kirchner H: Recent progress in the tumor necrosis factor-alpha field. Int Arch Allergy Immunol 1996;111:199-209.

    Article  CAS  PubMed  Google Scholar 

  8. Wilson AG, de Vries N, Pociot F, di Giovine FS, van der Putte LB, Duff GW: An allelic polymorphism within the human tumor necrosis factor alpha promoter region is strongly associated with HLA A1, B8, and DR3 alleles. J Exp Med 1993;177:557-560.

    Article  CAS  PubMed  Google Scholar 

  9. Mira JP, Cariou A, Grall F, Delclaux C, Losser MR, Heshmati F, Cheval C, Monchi M, Teboul JL, Riché F, Leleu G, Arbibe L, Mignon A, Delpech M, Dhainaut JF: Association of TNF2, a TNF-alpha promoter polymorphism, with septic shock susceptibility and mortality: a multicenter study. JAMA 1999;282:561-568.

    Article  CAS  PubMed  Google Scholar 

  10. Appoloni O, Dupont E, Vandercruys M, Andriens M, Duchateau J, Vincent JL: Association of tumor necrosis factor-2 allele with plasma tumor necrosis factor-alpha levels and mortality from septic shock. Am J Med 2001;110:486-488.

    Article  CAS  PubMed  Google Scholar 

  11. Stuber F, Udalova IA, Book M, Drutskaya LN, Kuprash DV, Turetskaya RL, Schade FU, Nedospasov SA: -308 tumor necrosis factor (TNF) polymorphism is not associated with survival in severe sepsis and is unrelated to lipopolysaccharide inducibility of the human TNF promoter. J Inflamm 1996;46:42-50.

    CAS  Google Scholar 

  12. O’Keefe GE, Hybki DL, Munford RS: The G-->A single nucleotide polymorphism at the -308 position in the tumor necrosis factor-alpha promoter increases the risk for severe sepsis after trauma. J Trauma 2002;52:817-825.

    Article  PubMed  Google Scholar 

  13. Tang GJ, Huang SL, Yien HW, Chen WS, Chi CW, Wu CW, Lui WY, Chiu JH, Lee TY: Tumor necrosis factor gene polymorphism and septic shock in surgical infection. Crit Care Med 2000;28:2733-2736.

    Article  CAS  PubMed  Google Scholar 

  14. Louis E, Franchimont D, Piron A, Gevaert Y, Schaaf-Lafontaine N, Roland S Mahieu P, Malaise M, De Groote D, Louis R, Belaiche J: Tumour necrosis factor (TNF) gene polymorphism influences TNF-alpha production in lipopolysaccharide (LPS)-stimulated whole blood cell culture in healthy humans. Clin Exp Immunol 1998;113:401-406.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Wilson AG, Symons JA, McDowell TL, McDevitt HO, Duff GW: Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation. Proc Natl Acad Sci USA. 1997;94:3195-3199.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Kothari N, Bogra J, Abbas H, Kohli M, Malik A, Kothari D, Srivastava S, Singh PK: Tumor necrosis factor gene polymorphism results in high TNF level in sepsis and septic shock. Cytokine 2013;61:676-681.

    Article  CAS  PubMed  Google Scholar 

  17. Brinkman BM, Zuijdeest D, Kaijzel EL, Breedveld FC, Verweij CL: Relevance of the tumor necrosis factor alpha (TNF alpha) -308 promoter polymorphism in TNF alpha gene regulation. J Inflamm 1996;46:32-41.

    CAS  Google Scholar 

  18. Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA Schein RM, Sibbald WJ: Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 1992;101:1644-1655.

    Article  CAS  PubMed  Google Scholar 

  19. Allen RA, Lee EM, Roberts DH, Park BK, Pirmohamed M: Polymorphisms in the TNF-alpha and TNF-receptor genes in patients with coronary artery disease. Eur J Clin Invest 2001;31:843-851.

    Article  CAS  PubMed  Google Scholar 

  20. Majetschak M, Flohe S, Obertacke U, Schroder J, Staubach K, Nast-Kolb D, Schade FU, Stuber F: Relation of a TNF gene polymorphism to severe sepsis in trauma patients. Ann Surg 1999;230:207-214.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Duan ZX, Gu W, Zhang LY, Jiang DP, Zhou J, Du DY, Zen L, Chen KH, Liu Q, Jiang JX: Tumor necrosis factor alpha gene polymorphism is associated with the outcome of trauma patients in Chinese Han population. J Trauma 2011;70:954-958.

    Article  CAS  PubMed  Google Scholar 

  22. Bittar MN, Carey JA, Barnard JB, Pravica V, Deiraniya AK, Yonan N, Hutchinson IV: Tumor necrosis factor alpha influences the inflammatory response after coronary surgery. Ann Thorac Surg 2006;81:132-137.

    Article  PubMed  Google Scholar 

  23. Majetschak M, Obertacke U, Schade FU, Bardenheuer M, Voggenreiter G, Bloemeke B, Heesen M: Tumor necrosis factor gene polymorphisms, leukocyte function, and sepsis susceptibility in blunt trauma patients. Clin Diagn Lab Immunol 2002;9:1205-1211.

    CAS  PubMed Central  PubMed  Google Scholar 

  24. Read RC, Teare DM, Pridmore AC, Naylor SC, Timms JM, Kaczmarski EB, Borrow R, Wilson AG: The tumor necrosis factor polymorphism TNF (-308) is associated with susceptibility to meningococcal sepsis, but not with lethality. Crit Care Med 2009;37:1237-1243.

    Article  CAS  PubMed  Google Scholar 

  25. Strey CW, Marquez-Pinilla RM, Markiewski MM, Siegmund B, Oppermann E, John Lambris JD, Bechstein WO: Early post-operative measurement of cytokine plasma levels combined with pre-operative bilirubin levels identify high-risk patients after liver resection. Int J Mol Med 2011;27:447-454.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Jacob CO, Fronek Z, Lewis GD, Koo M, Hansen JA, McDevitt HO: Heritable major histocompatibility complex class II–associated differences in production of tumor necrosis factor alpha: relevance to genetic predisposition to systemic lupus erythematosus. Proc Natl Acad Sci USA 1990;87:1233-1237.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Hack CE, De Groot ER, Felt-Bersma RJ, Nuijens JH, Strack Van Schijndel RJ, Eerenberg-Belmer AJ, Eerenberg-Belmer AJ, Thijs LG, Aarden LA: Increased plasma levels of interleukin-6 in sepsis. Blood 1989;74:1704-1710.

    CAS  PubMed  Google Scholar 

  28. Damas P, Ledoux D, Nys M, Vrindts Y, De Groote D, Franchimont P, Lamy M: Cytokine serum level during severe sepsis in human IL-6 as a marker of severity. Ann Surg 1992;215:356-362.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Hack CE, Hart M, van Schijndel RJ, Eerenberg AJ, Nuijens JH, Thijs LG, Aarden LA: Interleukin-8 in sepsis: relation to shock and inflammatory mediators. Infect Immun 1992;60:2835-2842.

    CAS  PubMed Central  PubMed  Google Scholar 

  30. Giannoudis PV, Smith MR, Evans RT, Bellamy MC, Guillou PJ: Serum CRP and IL-6 levels after trauma. Not predictive of septic complications in 31 patients. Acta Orthop Scand 1998;69:184-188.

    Article  CAS  PubMed  Google Scholar 

  31. Majetschak M, Krehmeier U, Ostroverkh L, Blömeke B, Schäfer M: Alterations in leukocyte function following surgical trauma: differentiation of distinct reaction types and association with tumor necrosis factor gene polymorphisms. Clin Diagn Lab Immunol 2005;12:296-303.

    CAS  PubMed Central  PubMed  Google Scholar 

  32. Tang R, Chen HH, Wang YL, Changchien CR, Chen JS, Hsu KC, Chiang JM, Wang JY: Risk factors for surgical site infection after elective resection of the colon and rectum: a single-center prospective study of 2,809 consecutive patients. Ann Surg 2001;234:181-189.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Offner PJ, Moore EE, Biffl WL: Male gender is a risk factor for major infections after surgery. Arch Surg 1999;134:935-940.

    Article  CAS  PubMed  Google Scholar 

  34. Velasco E, Thuler LC, Martins CA, Dias LM, Conalves VM: Risk factors for infectious complications after abdominal surgery for malignant disease. Am J Infect Control 1996;24:1-6.

    Article  CAS  PubMed  Google Scholar 

  35. Schro ̈der J, Kahlke V, Staubach KH, Zabel P, Stüber F: Gender differences in human sepsis. Arch Surg 1998;133:1200-1205.

  36. Eachempati SR, Hydo L, Barie PS: Gender-based differences in outcome in patients with sepsis. Arch Surg 1999;134:1342-1347.

    Article  CAS  PubMed  Google Scholar 

  37. Wichmann MW, Inthorn D, Andress HJ, Schildberg FW: Incidence and mortality of severe sepsis in surgical intensive care patients: the influence of patient gender on disease process and outcome. Intensive Care Med 2000;26:167-172.

    Article  CAS  PubMed  Google Scholar 

  38. Ansari MZ, Collopy BT, Hart WG, Carson NJ, Chandraraj EJ: In-hospital mortality and associated complications after bowel surgery in Victorian public hospitals. Aust N Z J Surg 2000;70:6-10.

    Article  CAS  PubMed  Google Scholar 

  39. Vogel TR, Dombrovskiy VY, Carson JL, Graham AM, Lowry SF: Postoperative sepsis in the United States. Ann Surg 2010;252:1065-1071.

    Article  PubMed Central  PubMed  Google Scholar 

  40. Hensler T, Heidecke CD, Hecker H, Heeg K, Bartels H, Zantl N, Wagner H, Siewert JR, Holzmann B: Increased Susceptibility to Postoperative Sepsis in Patients with Impaired Monocyte IL-12 Production. J Immunol 1998;161:2655-2659.

    CAS  PubMed  Google Scholar 

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Acknowledgments

The authors are thankful to the Council of Science and Technology, Government of Uttar Pradesh, Lucknow, India, for financially supporting the study (grant letter no. CST/SERPD/D-783 dated 01-07-2011).

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The authors declare that they have no competing interests.

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Correspondence to Rajeshwar Nath Srivastava.

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Baghel, K., Srivastava, R.N., Chandra, A. et al. TNF-α, IL-6, and IL-8 Cytokines and Their Association with TNF-α-308 G/A Polymorphism and Postoperative Sepsis. J Gastrointest Surg 18, 1486–1494 (2014). https://doi.org/10.1007/s11605-014-2574-5

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