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. 2001;4(3):209–215. doi: 10.1023/A:1013222407924

Cytokine Polymorphisms and Susceptibility to Severe Infectious Diseases

Jean-Daniel Chiche 1, Shidasp Siami 1, Jean-FrançDois Dhainaut 1, Jean-Paul Mira 2
PMCID: PMC7144473  PMID: 32288621

Abstract

Cytokines are key regulators of the host response to infection, controlling the inflammatory reaction which is an essential component of the defense mechanisms. The major importance of these proteins in the pathogenesis and outcome of infectious diseases has been clearly demonstrated. In humans, there is increasing evidence that the host's cytokine response is genetically determined and that the genetic variability of cytokines underlies the complexity of interindividual differences in the immune response to micro organism invasions. We review the influence of host cytokine gene on the susceptibility to and the severity of parasitic, bacterial and viral infections. Proinflammatory cytokine polymorphisms are discussed in detail because of their importance in the course of severe infections such as meningococcal disease, cerebral malaria and septic shock. Genetic variants of the IL-10 gene, an antiinflammatory cytokine appear to be responsible for an uncontrolled and intense CARS and may have also dramatic consequences as an overwhelming inflammatory response. Our greater understanding of the genetic factors that influence mortality and morbidity of infectious diseases will permit identification of genomic markers which may be required for risk stratification of patients targeted for novel immunomodulatory treatments helping clinicians to select the most appropriate treatment options for their patients.

Keywords: sepsis, inflammation-cytokines, polymorphisms, genetic predisposition to disease

References

  • 1.Bion JF. Susceptibility to critical illness: reserve, response and therapy. Intensive Care Med. 2000;26(Suppl1):S57–63. doi: 10.1007/s001340051120. [DOI] [PubMed] [Google Scholar]
  • 2.Adrie C, Pinsky MR. The inflammatory balance in human sepsis. Intensive Care Med. 2000;26:364–375. doi: 10.1007/s001340051169. [DOI] [PubMed] [Google Scholar]
  • 3.Dinarello CA. Proinflammatory cytokines. Chest. 2000;118:503–558. doi: 10.1378/chest.118.2.503. [DOI] [PubMed] [Google Scholar]
  • 4.Osterrieder N, Wolf E. Lessons from gene knockouts. Rev Sci Tech. 1998;17:351–364. doi: 10.20506/rst.17.1.1100. [DOI] [PubMed] [Google Scholar]
  • 5.Ladel CH, Blum C, Dreher A, Reifenberg K, Kopf M, Kaufmann SH. Lethal tuberculosis in interleukin-6-deficient mutant mice. Infect Immun. 1997;65:4843–4849. doi: 10.1128/iai.65.11.4843-4849.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Van Enckevort FH, Netea MG, Hermus AR, Sweep CG, Meis JF, Van Der Meer JW, Kullberg BJ. Increased susceptibility to systemic candidiasis in interleukin-6 deficient mice. Med Mycol. 1999;37:419–426. doi: 10.1046/j.1365-280x.1999.00247.x. [DOI] [PubMed] [Google Scholar]
  • 7.Murray PJ, Young RA. Increased antimycobacterial immunity in interleukin-10-deficient mice. Infect Immun. 1999;67:3087–3395. doi: 10.1128/iai.67.6.3087-3095.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Bidwell J, Keen L, Gallagher G, Kimberly R, Huizinga T, McDermott MF, Oksenberg J, McNicholl J, Pociot F, Hardt C, D'Alfonso S. Cytokine gene polymorphism in human disease: on-line databases. Genes Immun. 1999;1:3–19. doi: 10.1038/sj.gene.6363645. [DOI] [PubMed] [Google Scholar]
  • 9.Papadakis KA, Targan SR. Tumor necrosis factor: biology and therapeutic inhibitors. Gastroenterology. 2000;119:1148–1157. doi: 10.1053/gast.2000.18160. [DOI] [PubMed] [Google Scholar]
  • 10.Sean Riminton D, Korner H, Strickland DH, Lemckert FA, Pollard JD, Sedgwick JD. Challenging cytokine redundancy: inflammatory cell movement and clinical course of experimental autoimmune encephalomyelitis are normal in lymphotoxin-deficient, but not tumor necrosis factor-deficient, mice. J Exp Med. 1998;187:1517–1528. doi: 10.1084/jem.187.9.1517. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Tracey KJ, Cerami A. Tumor necrosis factor: a pleiotropic cytokine and therapeutic target. Ann Rev Med. 1994;45:491–503. doi: 10.1146/annurev.med.45.1.491. [DOI] [PubMed] [Google Scholar]
  • 12.Takashima K, Tateda K, Matsumoto T, Iizawa Y, Nakao M, Yamaguchi K. Role of tumor necrosis factor alpha in pathogenesis of pneumococcal pneumonia in mice. Infect Immun. 1997;65:257–260. doi: 10.1128/iai.65.1.257-260.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Brauner JS, Rohde LE, Clausell N. Circulating endothelin-1 and tumor necrosis factor-alpha: early predictors of mortality in patients with septic shock. Intens Care Med. 2000;26:305–313. doi: 10.1007/s001340051154. [DOI] [PubMed] [Google Scholar]
  • 14.Dofferhoff AS, Bom VJ, de Vries-Hospers HG, Van Ingen J, Vd Meer J, Hazenberg BP, Mulder PO, Weits J. Patterns of cytokines, plasma endotoxin, plasminogen activator inhibitor, and acute-phase proteins during the treatment of severe sepsis in humans. Crit Care Med. 1992;20:185–192. doi: 10.1097/00003246-199202000-00007. [DOI] [PubMed] [Google Scholar]
  • 15.Molvig J, Pociot F, Worsaae H, Wogensen LD, Baek L, Christensen P, Mandrup-Poulsen T, Andersen K, Madsen P, Dyerberg J, et al. Dietary supplementation with omega-3-polyunsaturated fatty acids decreases mononuclear cell proliferation and interleukin-1 beta content but not monokine secretion in healthy and insulin-dependent diabetic individuals. Scand J Immunol. 1991;34:399–410. doi: 10.1111/j.1365-3083.1991.tb01563.x. [DOI] [PubMed] [Google Scholar]
  • 16.Westendorp RG, Langermans JA, Huizinga TW, Verweij CL, Sturk A. Genetic influence on cytokine production in meningococcal disease. Lancet. 1997;349:1912–1993. doi: 10.1016/s0140-6736(05)63910-4. [DOI] [PubMed] [Google Scholar]
  • 17.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;94:3195–3319. doi: 10.1073/pnas.94.7.3195. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Abraham LJ, Kroeger K. I. mpact of the-308 TNF promoter polymorphism on the transcriptional regulation of the TNF gene: relevance to disease. J Leukoc Biol. 1999;66:562–566. doi: 10.1002/jlb.66.4.562. [DOI] [PubMed] [Google Scholar]
  • 19.Knight JC, Kwiatkowski D. Inherited variability of tumor necrosis factor production and susceptibility to infectious disease. Proc Assoc Am Physicians. 1999;111:290–328. doi: 10.1046/j.1525-1381.1999.99237.x. [DOI] [PubMed] [Google Scholar]
  • 20.Warzocha, Ribeiro P, Bienvenu J, Roy P, Charlot C, Rigal D, Coiffier B, Salles G. Genetic polymorphisms in the tumor necrosis factor locus influence non-Hodgkin's lymphoma outcome. Blood. 1998;91:3574–3581. [PubMed] [Google Scholar]
  • 21.Hajeer AH, Hutchinson IV. TNF-alpha gene polymorphism: clinical and biological implications. Microsc Res Tech. 2000;50:216–228. doi: 10.1002/1097-0029(20000801)50:3<216::AID-JEMT5>3.0.CO;2-Q. [DOI] [PubMed] [Google Scholar]
  • 22.McGuire W, Knight JC, Hill AV, Allsopp CE, Greenwood BM, Kwiatkowski D. Severe malarial anemia and cerebral malaria are associated with different tumor necrosis factor promoter alleles. J Infect Dis. 1999;179:287–290. doi: 10.1086/314533. [DOI] [PubMed] [Google Scholar]
  • 23.Knight JC, Udalova I, Hill AV, Greenwood BM, Peshu N, Marsh K, Kwiatkowski D. A polymorphism that affects OCT-1 binding to the TNF promoter region is associated with severe malaria. Nat Genet. 1999;22:145–150. doi: 10.1038/9649. [DOI] [PubMed] [Google Scholar]
  • 24.Cabrera M, Shaw MA, Sharples C, Williams H, Castes M, Convit J, Blackwell JM. Polymorphism in tumor necrosis factor genes associates with mucocutaneous leishmaniasis. J Exp Med. 1995;182:1259–1264. doi: 10.1084/jem.182.5.1259. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Conway DJ, Holland MJ, Bailey RL, Campbell AE, Mahdi OS, Jennings R, Mbena E, Mabey DC. Scarring trachoma is associated with polymorphism in the tumor necrosis factor alpha (TNF-alpha) gene promoter and with elevated TNF-alpha levels in tear fluid. Infect Immun. 1997;65:1003–1106. doi: 10.1128/iai.65.3.1003-1006.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Kanerva M, Vaheri A, Mustonen J, Partanen J. High-producer allele of tumour necrosis factor-alpha is part of the susceptibility MHC haplotype in severe puumala virus-induced nephropathia epidemica. Scand J Infect Dis. 1998;30:532–554. doi: 10.1080/00365549850161629. [DOI] [PubMed] [Google Scholar]
  • 27.Nadel S, Newport MJ, Booy R, Levin M. Variation in the tumor necrosis factor-alpha gene promoter region may be associated with death from meningococcal disease. J Infect Dis. 1996;174:878–880. doi: 10.1093/infdis/174.4.878. [DOI] [PubMed] [Google Scholar]
  • 28.Nuntayanuwat S, Dharakul T, Chaowagul W, Songsivilai S. Polymorphism in the promoter region of tumor necrosis factor-alpha gene is associated with severe meliodosis. Hum Immunol. 1999;60:979–983. doi: 10.1016/s0198-8859(99)00073-7. [DOI] [PubMed] [Google Scholar]
  • 29.Mira JP, Cariou A, Grall F, Delclaux C, Losser MR, Heshmati F, Cheval C, Monchi M, Teboul JL, Riche F, Leleu G, Arbibe L, Mignon A, Delpech M, Dhainaut J F. Association of TNF2, a TNF-alpha promoter polymorphism, with septic shock susceptibility and mortality: a multicenter study. JAMA. 1999;282:561–568. doi: 10.1001/jama.282.6.561. [DOI] [PubMed] [Google Scholar]
  • 30.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;28:2733–2776. doi: 10.1097/00003246-200008000-00008. [DOI] [PubMed] [Google Scholar]
  • 31.Stuber F, Petersen M, Bokelmann F, Schade U. A genomic polymorphism within the tumor necrosis factor locus influences plasma tumor necrosis factor-alpha concentrations and outcome of patients with severe sepsis. Crit Care Med. 1996;24:381–434. doi: 10.1097/00003246-199603000-00004. [DOI] [PubMed] [Google Scholar]
  • 32.Skoog T, Van'T Hooft FM, Kallin B, Jovinge S, Boquist S, Nilsson J, Eriksson P, Hamsten A. A common functional polymorphism (C→A substitution at position - 863) in the promoter region of the tumour necrosis factor-alpha (TNFalpha) gene associated with reduced circulating levels of TNF-alpha. Hum Mol Genet. 1999;8:1443–1449. doi: 10.1093/hmg/8.8.1443. [DOI] [PubMed] [Google Scholar]
  • 33.Pociot F, Molvig J, Wogensen L, Worsaae H, Dalboge H, Baek L, Nerup J. A tumour necrosis factor beta gene polymorphism in relation to monokine secretion and insulin-dependent diabetes mellitus. Scand J Immunol. 1991;33:37–49. doi: 10.1111/j.1365-3083.1991.tb02490.x. [DOI] [PubMed] [Google Scholar]
  • 34.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. 1995;46:42–50. [PubMed] [Google Scholar]
  • 35.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. doi: 10.1097/00000658-199908000-00011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Sahoo S, Kang S, Supran S, Saloman R, Wolfe H, Freeman RB. Tumor necrosis factor genetic polymorphisms correlate with infections after renal transplantation. Transplantation. 2000;69:880–884. doi: 10.1097/00007890-200003150-00036. [DOI] [PubMed] [Google Scholar]
  • 37.Freeman RB, Tran CL, Mattoli J, Patel K, Supran S, Basile FG, Krishnamurthy S, Aihara R. Tumor necrosis factor genetic polymorphisms correlate with infections after liver transplantation. Transplantation. 1999;67:1005–1110. doi: 10.1097/00007890-199904150-00012. [DOI] [PubMed] [Google Scholar]
  • 38.Dinarello CA. The role of the interleukin-1-receptor antagonist in blocking inflammation mediated by interleukin-1. N Engl J Med. 2000;343:732–774. doi: 10.1056/NEJM200009073431011. [DOI] [PubMed] [Google Scholar]
  • 39.Hirsch E, Irikura VM, Paul SM, Hirsh D. Functions of interleukin1 receptor antagonist in gene knockout and overproducing mice. Proc Natl Acad Sci USA. 1996;93:11008–11113. doi: 10.1073/pnas.93.20.11008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Tarlow JK, Blakemore AI, Lennard A, Solari R, Hughes HN, Steinkasserer A, Duff GW. Polymorphism in human IL-1 receptor antagonist gene intron 2 is caused by variable numbers of an 86-bp tandem repeat. Hum Genet. 1993;91:403–444. doi: 10.1007/BF00217368. [DOI] [PubMed] [Google Scholar]
  • 41.Pociot F, Molvig J, Wogensen L, Worsaae H, Nerup J. A TaqI polymorphism in the human interleukin-1 beta (IL-1 beta) gene correlates with IL-1 beta secretion in vitro. Eur J Clin Invest. 1992;22:396–402. doi: 10.1111/j.1365-2362.1992.tb01480.x. [DOI] [PubMed] [Google Scholar]
  • 42.Santtila S, Savinainen K, Hurme M. Presence of the IL-1RA allele 2 (IL1RN*2) is associated with enhanced IL-1beta production in vitro. Scand J Immunol. 1998;47:195–218. doi: 10.1046/j.1365-3083.1998.00300.x. [DOI] [PubMed] [Google Scholar]
  • 43.Fang XM, Schroder S, Hoeft A, Stuber F. Comparison of two polymorphisms of the interleukin-1 gene family: interleukin-1 receptor antagonist polymorphism contributes to susceptibility to severe sepsis. Crit Care Med. 1999;27:1330–1334. doi: 10.1097/00003246-199907000-00024. [DOI] [PubMed] [Google Scholar]
  • 44.El-Omar EM, Carrington M, Chow WH, McColl KE, Bream JH, Young HA, Herrera J, Lissowska J, Yuan CC, Rothman N, Lanyon G, Martin M, Fraumeni JF, Rabkin CS. Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature. 2000;404:398–402. doi: 10.1038/35006081. [DOI] [PubMed] [Google Scholar]
  • 45.Read RC, Camp NJ, Di Giovine FS, Borrow R, Kaczmarski EB, Chaudhary AG, Fox AJ, Duff GW. An interleukin-1 genotype is associated with fatal outcome of meningococcal disease. J Infect Dis. 2000;182:1557–1560. doi: 10.1086/315889. [DOI] [PubMed] [Google Scholar]
  • 46.Dalrymple SA, Slattery R, Aud DM, Krishma M, Lucian LA, Murray R. Interleukin-6 is required for a protective immune response to systemic Escherichia coli infection. Infect Immun. 1996;64:3231–3325. doi: 10.1128/iai.64.8.3231-3235.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Khalil A, Tullus K, Bartfai T, Bakhiet M, Jaremko G, Brauner A. Renal cytokine responses in acute Escherichia coli pyelonephritis in IL-6-deficient mice. Clin Exp Immunol. 2000;122:200–226. doi: 10.1046/j.1365-2249.2000.01377.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Olomolaiye O, Wood NA, Bidwell JL. A novel N1aIII polymorphism in the human IL-6 promoter. Eur J Immunogenet. 1998;25:267. [PubMed] [Google Scholar]
  • 49.Terry CF, Loukaci V, Green FR. Cooperative influence of genetic polymorphisms on interleukin 6 transcriptional regulation. J Biol Chem. 2000;275:18138–18144. doi: 10.1074/jbc.M000379200. [DOI] [PubMed] [Google Scholar]
  • 50.Aggarwal A, Baker CS, Evans TW, Haslam PL. G-CSF and IL-8 but not GM-CSF correlate with severity of pulmonary neutrophilia in acute respiratory distress syndrome. Eur Respir J. 2000;15:895–901. doi: 10.1034/j.1399-3003.2000.15e14.x. [DOI] [PubMed] [Google Scholar]
  • 51.Abul H, Abul A, Khan I, Mathew TC, Ayed A, Al-Athary E. Levels of IL-8 and myeloperoxidase in the lungs of pneumonia patients. Mol Cell Biochem. 2001;217:107–112. doi: 10.1023/A:1007264411006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Hull J, Thomson A, Kwiatkowski D. Association of respiratory syncytial virus bronchiolitis with the interleukin 8 gene region in UK families. Thorax. 2000;55:1023–1107. doi: 10.1136/thorax.55.12.1023. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Bone RC. Sir Isaac Newton, sepsis, SIRS, and CARS. Crit Care Med. 1996;24:1125–118. doi: 10.1097/00003246-199607000-00010. [DOI] [PubMed] [Google Scholar]
  • 54.Van Dissel JT, Van Langevelde P, Westendorp RG, Kwappenberg K, Frolich M. Anti-inflammatory cytokine profile and mortality in febrile patients. Lancet. 1998;351:950–993. doi: 10.1016/S0140-6736(05)60606-X. [DOI] [PubMed] [Google Scholar]
  • 55.Eskdale J, Gallagher G, Verweij CL, Keijsers V, Westendorp RG, Huizinga TW. Interleukin 10 secretion in relation to human IL-10 locus haplotypes. Proc Natl Acad Sci USA. 1998;95:9465–9470. doi: 10.1073/pnas.95.16.9465. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Hurme M, Lahdenpohja N, Santtila S. Gene polymorphisms of interleukins 1 and 10 in infectious and autoimmune diseases. Ann Med. 1998;30:469–473. doi: 10.3109/07853899809002488. [DOI] [PubMed] [Google Scholar]
  • 57.Gibson AW, Edberg JC, Wu J, Westendorp RG, Huizinga TW, Kimberly RP. Novel single nucleotide polymorphisms in the distal il-10 promoter affect il-10 production and enhance the risk of systemic lupus erythematosus. J Immunol. 2001;166:3915–3922. doi: 10.4049/jimmunol.166.6.3915. [DOI] [PubMed] [Google Scholar]
  • 58.Turner DM, Williams DM, Sankaran D, Lazarus M, Sinnott PJ, Hutchinson IV. An investigation of polymorphism in the interleukin-10 gene promoter. Eur J Immunogenet. 1997;24:1–8. doi: 10.1111/j.1365-2370.1997.tb00001.x. [DOI] [PubMed] [Google Scholar]
  • 59.Mozzato-Chamay N, Mahdi OS, Jallow O, Mabey DC, Bailey RL, Conway DJ. Polymorphisms in candidate genes and risk of scarring trachoma in a Chlamydia trachomatis- endemic population. J Infect Dis. 2000;182:1545–1558. doi: 10.1086/315891. [DOI] [PubMed] [Google Scholar]

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