Intensive Care Medicine

, Volume 34, Issue 4, pp 683–691 | Cite as

The human response to infection is associated with distinct patterns of interleukin 23 and interleukin 27 expression

  • Michael J. O’Dwyer
  • Arun K. Mankan
  • Mary White
  • Mathew W. Lawless
  • Patrick Stordeur
  • Brian O’Connell
  • Dermot P. Kelleher
  • Ross McManus
  • Thomas Ryan
Original

Abstract

Objective

The development and progression of severe sepsis is related to a deficiency in pro-inflammatory cytokine production, characterised by lesser IFNγ levels, which are not explained by variations in levels of the main putative regulator of IFNγ, namely IL-12. As alternative regulators of IFNγ may be of greater importance in human sepsis, we investigated the hypothesis that the development of severe sepsis is related to variations in IL-18, IL-23 and IL-27 gene expression.

Design and setting

A prospective observational trial in a mixed intensive care unit (ICU) and hospital wards in a university teaching hospital.

Patients and participants

Sixty-two ICU patients with severe sepsis, 13 bacteraemic patients with no acute critical illness, and 10 healthy controls.

Measurements and results

All subjects were assayed for IL-18, IL-23 and IL-27 mRNA levels in peripheral blood. IL-27 mRNA levels distinguished between the three groups, with levels highest in the ICU group, intermediate in the bacteraemic group and lowest in the control group. IL-23 distinguished between the groups, with levels lowest in the ICU group. In late sepsis IL-23 and TNFα mRNA levels were directly related. IL-18 mRNA levels did not distinguish between the patient groups.

Conclusions

We conclude that the deficient pro-inflammatory response in patients with sepsis is expansive and includes deficient IL-23 and excessive IL-27 gene expression. This provides further evidence that upregulation of a cytokine-based immune response is beneficial in sepsis.

Keywords

Sepsis syndrome Cytokines Reverse transcriptase polymerase chain reaction Helper T-cells 

Supplementary material

134_2007_968_MOESM1_ESM.doc (32 kb)
Electronic Supplementary Material (DOC 32K)

References

  1. 1.
    Docke WD, Randow F, Syrbe U, Krausch D, Asadullah K, Reinke P, Volk HD, Kox W (1997) Monocyte deactivation in septic patients: restoration by IFN-gamma treatment. Nat Med 3:678–681PubMedCrossRefGoogle Scholar
  2. 2.
    Pachot A, Monneret G, Brion A, Venet F, Bohe J, Bienvenu J, Mougin B, Lepape A (2005) Messenger RNA expression of major histocompatibility complex class II genes in whole blood from septic shock patients. Crit Care Med 33:31–38PubMedCrossRefGoogle Scholar
  3. 3.
    O'Dwyer MJ, Mankan AK, Stordeur P, O'Connell B, Duggan E, White M, Kelleher DP, McManus R, Ryan T (2006) The occurrence of severe sepsis and septic shock are related to distinct patterns of cytokine gene expression. Shock 26:544–550PubMedCrossRefGoogle Scholar
  4. 4.
    Szabo SJ, Sullivan BM, Peng SL, Glimcher LH (2003) Molecular mechanisms regulating Th1 immune responses. Annu Rev Immunol 21:713–758PubMedCrossRefGoogle Scholar
  5. 5.
    Oppmann B, Lesley R, Blom B, Timans JC, Xu Y, Hunte B, Vega F, Yu N, Wang J, Singh K, Zonin F, Vaisberg E, Churakova T, Liu M, Gorman D, Wagner J, Zurawski S, Liu Y, Abrams JS, Moore KW, Rennick D, de Waal-Malefyt R, Hannum C, Bazan JF, Kastelein RA (2000) Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 13:715–725PubMedCrossRefGoogle Scholar
  6. 6.
    Pflanz S, Timans JC, Cheung J, Rosales R, Kanzler H, Gilbert J, Hibbert L, Churakova T, Travis M, Vaisberg E, Blumenschein WM, Mattson JD, Wagner JL, To W, Zurawski S, McClanahan TK, Gorman DM, Bazan JF, de Waal Malefyt R, Rennick D, Kastelein RA (2002) IL-27, a heterodimeric cytokine composed of EBI3 and p28 protein, induces proliferation of naive CD4 (+) T cells. Immunity 16:779–790PubMedCrossRefGoogle Scholar
  7. 7.
    Hunter CA (2005) New IL-12-family members: IL-23 and IL-27, cytokines with divergent functions. Nat Rev Immunol 5:521–531PubMedCrossRefGoogle Scholar
  8. 8.
    Pachot A, Monneret G, Voirin N, Leissner P, Venet F, Bohe J, Payen D, Bienvenu J, Mougin B, Lepape A (2005) Longitudinal study of cytokine and immune transcription factor mRNA expression in septic shock. Clin Immunol 114:61–69PubMedCrossRefGoogle Scholar
  9. 9.
    Bjerre A, Brusletto B, Hoiby EA, Kierulf P, Brandtzaeg P (2004) Plasma interferon-gamma and interleukin-10 concentrations in systemic meningococcal disease compared with severe systemic Gram-positive septic shock. Crit Care Med 32:433–438PubMedCrossRefGoogle Scholar
  10. 10.
    Goldie AS, Fearon KC, Ross JA, Barclay GR, Jackson RE, Grant IS, Ramsay G, Blyth AS, Howie JC (1995) Natural cytokine antagonists and endogenous antiendotoxin core antibodies in sepsis syndrome. The Sepsis Intervention Group. JAMA 274:172–177PubMedCrossRefGoogle Scholar
  11. 11.
    Fu N, Drinnenberg I, Kelso J, Wu JR, Paabo S, Zeng R, Khaitovich P (2007) Comparison of protein and mRNA expression evolution in humans and chimpanzees. PLoS ONE 2:e216PubMedCrossRefGoogle Scholar
  12. 12.
    American College of Chest Physicians, Society of Critical Care Medicine Consensus Conference (1992) Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 20:864–874CrossRefGoogle Scholar
  13. 13.
    Vincent JL, Moreno R, Takala J, Willatts S, De Mendonca A, Bruining H, Reinhart CK, Suter PM, Thijs LG (1996) The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med 22:707–710PubMedCrossRefGoogle Scholar
  14. 14.
    Le Gall JR, Lemeshow S, Saulnier F (1993) A new Simplified Acute Physiology Score (SAPS II) based on a European/North American multicenter study. JAMA 270:2957–2963PubMedCrossRefGoogle Scholar
  15. 15.
    Stordeur P, Poulin LF, Craciun L, Zhou L, Schandene L, de Lavareille A, Goriely S, Goldman M (2002) Cytokine mRNA quantification by real-time PCR. J Immunol Methods 259:55–64PubMedCrossRefGoogle Scholar
  16. 16.
    Uhlig HH, McKenzie BS, Hue S, Thompson C, Joyce-Shaikh B, Stepankova R, Robinson N, Buonocore S, Tlaskalova-Hogenova H, Cua DJ, Powrie F (2006) Differential activity of IL-12 and IL-23 in mucosal and systemic innate immune pathology. Immunity 25:309–318PubMedCrossRefGoogle Scholar
  17. 17.
    Parham C, Chirica M, Timans J, Vaisberg E, Travis M, Cheung J, Pflanz S, Zhang R, Singh KP, Vega F, To W, Wagner J, O'Farrell AM, McClanahan T, Zurawski S, Hannum C, Gorman D, Rennick DM, Kastelein RA, de Waal Malefyt R, Moore KW (2002) A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R. J Immunol 168:5699–5708PubMedGoogle Scholar
  18. 18.
    Happel KI, Zheng M, Young E, Quinton LJ, Lockhart E, Ramsay AJ, Shellito JE, Schurr JR, Bagby GJ, Nelson S, Kolls JK (2003) Cutting edge: roles of Toll-like receptor 4 and IL-23 in IL-17 expression in response to Klebsiella pneumoniae infection. J Immunol 170:4432–4436PubMedGoogle Scholar
  19. 19.
    Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B (2006) TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24:179–189PubMedCrossRefGoogle Scholar
  20. 20.
    Ye P, Rodriguez FH, Kanaly S, Stocking KL, Schurr J, Schwarzenberger P, Oliver P, Huang W, Zhang P, Zhang J, Shellito JE, Bagby GJ, Nelson S, Charrier K, Peschon JJ, Kolls JK (2001) Requirement of interleukin 17 receptor signaling for lung CXC chemokine and granulocyte colony-stimulating factor expression, neutrophil recruitment, and host defense. J Exp Med 194:519–527PubMedCrossRefGoogle Scholar
  21. 21.
    Colgan J, Rothman P (2006) All in the family: IL-27 suppression of T (H)-17 cells. Nat Immunol 7:899–901PubMedCrossRefGoogle Scholar
  22. 22.
    Yen D, Cheung J, Scheerens H, Poulet F, McClanahan T, McKenzie B, Kleinschek MA, Owyang A, Mattson J, Blumenschein W, Murphy E, Sathe M, Cua DJ, Kastelein RA, Rennick D (2006) IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J Clin Invest 116:1310–1316PubMedCrossRefGoogle Scholar
  23. 23.
    Chen Y, Langrish CL, McKenzie B, Joyce-Shaikh B, Stumhofer JS, McClanahan T, Blumenschein W, Churakovsa T, Low J, Presta L, Hunter CA, Kastelein RA, Cua DJ (2006) Anti-IL-23 therapy inhibits multiple inflammatory pathways and ameliorates autoimmune encephalomyelitis. J Clin Invest 116:1317–1326PubMedCrossRefGoogle Scholar
  24. 24.
    Villarino A, Hibbert L, Lieberman L, Wilson E, Mak T, Yoshida H, Kastelein RA, Saris C, Hunter CA (2003) The IL-27R (WSX-1) is required to suppress T cell hyperactivity during infection. Immunity 19:645–655PubMedCrossRefGoogle Scholar
  25. 25.
    Wirtz S, Tubbe I, Galle PR, Schild HJ, Birkenbach M, Blumberg RS, Neurath MF (2006) Protection from lethal septic peritonitis by neutralizing the biological function of interleukin 27. J Exp Med 203:1875–1881PubMedCrossRefGoogle Scholar
  26. 26.
    Batten M, Li J, Yi S, Kljavin NM, Danilenko DM, Lucas S, Lee J, de Sauvage FJ, Ghilardi N (2006) Interleukin 27 limits autoimmune encephalomyelitis by suppressing the development of interleukin 17-producing T cells. Nat Immunol 7:929–936PubMedCrossRefGoogle Scholar
  27. 27.
    Stumhofer JS, Laurence A, Wilson EH, Huang E, Tato CM, Johnson LM, Villarino AV, Huang Q, Yoshimura A, Sehy D, Saris CJ, O'Shea JJ, Hennighausen L, Ernst M, Hunter CA (2006) Interleukin 27 negatively regulates the development of interleukin 17-producing T helper cells during chronic inflammation of the central nervous system. Nat Immunol 7:937–945PubMedCrossRefGoogle Scholar
  28. 28.
    Happel KI, Dubin PJ, Zheng M, Ghilardi N, Lockhart C, Quinton LJ, Odden AR, Shellito JE, Bagby GJ, Nelson S, Kolls JK (2005) Divergent roles of IL-23 and IL-12 in host defense against Klebsiella pneumoniae. J Exp Med 202:761–769PubMedCrossRefGoogle Scholar
  29. 29.
    Altare F, Lammas D, Revy P, Jouanguy E, Doffinger R, Lamhamedi S, Drysdale P, Scheel-Toellner D, Girdlestone J, Darbyshire P, Wadhwa M, Dockrell H, Salmon M, Fischer A, Durandy A, Casanova JL, Kumararatne DS (1998) Inherited interleukin 12 deficiency in a child with bacille Calmette-Guerin and Salmonella enteritidis disseminated infection. J Clin Invest 102:2035–2040PubMedCrossRefGoogle Scholar
  30. 30.
    Altare F, Durandy A, Lammas D, Emile JF, Lamhamedi S, Le Deist F, Drysdale P, Jouanguy E, Doffinger R, Bernaudin F, Jeppsson O, Gollob JA, Meinl E, Segal AW, Fischer A, Kumararatne D, Casanova JL (1998) Impairment of mycobacterial immunity in human interleukin-12 receptor deficiency. Science 280:1432–1435PubMedCrossRefGoogle Scholar
  31. 31.
    Jong R de, Altare F, Haagen IA, Elferink DG, Boer T, van Breda Vriesman PJ, Kabel PJ, Draaisma JM, van Dissel JT, Kroon FP, Casanova JL, Ottenhoff TH (1998) Severe mycobacterial and Salmonella infections in interleukin-12 receptor-deficient patients. Science 280:1435–1438CrossRefGoogle Scholar
  32. 32.
    Fieschi C, Bosticardo M, de Beaucoudrey L, Boisson-Dupuis S, Feinberg J, Santos OF, Bustamante J, Levy J, Candotti F, Casanova JL (2004) A novel form of complete IL-12/IL-23 receptor beta1 deficiency with cell surface-expressed nonfunctional receptors. Blood 104:2095–2101PubMedCrossRefGoogle Scholar
  33. 33.
    Filipe-Santos O, Bustamante J, Chapgier A, Vogt G, de Beaucoudrey L, Feinberg J, Jouanguy E, Boisson-Dupuis S, Fieschi C, Picard C, Casanova JL (2006) Inborn errors of IL-12/23- and IFN-gamma-mediated immunity: molecular, cellular, and clinical features. Semin Immunol 18:347–361PubMedCrossRefGoogle Scholar
  34. 34.
    Hue S, Ahern P, Buonocore S, Kullberg MC, Cua DJ, McKenzie BS, Powrie F, Maloy KJ (2006) Interleukin-23 drives innate and T cell-mediated intestinal inflammation. J Exp Med 203:2473–2483PubMedCrossRefGoogle Scholar
  35. 35.
    Nakos G, Malamou-Mitsi VD, Lachana A, Karassavoglou A, Kitsiouli E, Agnandi N, Lekka ME (2002) Immunoparalysis in patients with severe trauma and the effect of inhaled interferon-gamma. Crit Care Med 30:1488–1494PubMedCrossRefGoogle Scholar
  36. 36.
    Tschoeke SK, Oberholzer A, Moldawer LL (2006) Interleukin-18: a novel prognostic cytokine in bacteria-induced sepsis. Crit Care Med 34:1225–1233PubMedCrossRefGoogle Scholar
  37. 37.
    Moreno SE, Alves-Filho JC, Alfaya TM, da Silva JS, Ferreira SH, Liew FY (2006) IL-12, but not IL-18, is critical to neutrophil activation and resistance to polymicrobial sepsis induced by cecal ligation and puncture. J Immunol 177:3218–3224PubMedGoogle Scholar
  38. 38.
    Hack CJ (2004) Integrated transcriptome and proteome data: the challenges ahead. Brief Funct Genomic Proteomic 3:212–219PubMedCrossRefGoogle Scholar
  39. 39.
    Gestel A van, Bakker J, Veraart CP, van Hout BA (2004) Prevalence and incidence of severe sepsis in Dutch intensive care units. Crit Care 8:R153–R162CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Michael J. O’Dwyer
    • 1
    • 2
  • Arun K. Mankan
    • 2
  • Mary White
    • 1
  • Mathew W. Lawless
    • 2
  • Patrick Stordeur
    • 3
  • Brian O’Connell
    • 4
  • Dermot P. Kelleher
    • 2
  • Ross McManus
    • 2
  • Thomas Ryan
    • 1
  1. 1.Department of AnaesthesiaSt James’s HospitalDublinIreland
  2. 2.Department of Clinical MedicineTrinity CollegeDublinIreland
  3. 3.Department of Immunology-Haematology-Transfusion, Hôpital ErasmeUniversité Libre de BruxellesBrusselsBelgium
  4. 4.Department of Clinical MicrobiologySt James’s HospitalDublinIreland

Personalised recommendations