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Intensive Care Medicine
Published in: Intensive Care Medicine 4/2010

Open Access 01-04-2010 | Original

Soluble ST2 plasma concentrations predict mortality in severe sepsis

Authors: Jacobien J. Hoogerwerf, Michael W. T. Tanck, Marieke A. D. van Zoelen, Xavier Wittebole, Pierre-François Laterre, Tom van der Poll

Published in: Intensive Care Medicine | Issue 4/2010

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Abstract

Purpose

Patients with sepsis—after surviving the initial hyperinflammatory phase—display features consistent with immunosuppression, including hyporesponsiveness of immunocompetent cells to bacterial agents. Immunosuppression is thought to be facilitated by negative regulators of toll-like receptors, including membrane-bound ST2. We investigated the release of soluble ST2 (sST2), a decoy receptor that inhibits membrane-bound ST2 signaling, during sepsis.

Methods

The study population comprised 95 patients with severe sepsis admitted to one of two intensive care units (ICUs) at the day the diagnosis of severe sepsis was made. Blood was obtained daily from admission (day 0) until day 7 and finally at day 14. Twenty-four healthy subjects served as controls. sST2 and cytokines were measured in serum.

Results

Mortality among patients was 34% in the ICU and 45% in the hospital. On admission, sepsis patients had higher sST2 levels [10,989 (7,871–15,342) pg/ml, geometric mean (95% confidence interval, CI)] than controls [55 (20–145) pg/ml, P < 0.0001]. Serum sST2 remained elevated in patients from day 0 to 14 and correlated with disease severity scores (P < 0.001) and cytokine levels on day 0 and during course of disease (P < 0.0001). Nonsurvivors displayed elevated sST2 levels compared with survivors of the intensive care unit (P < 0.0001).

Conclusions

Sepsis results in sustained elevation of serum sST2 levels, which correlates with disease severity and mortality.
Literature
1.
2.
Hotchkiss RS, Karl IE (2003) The pathophysiology and treatment of sepsis. N Engl J Med 348:138–150CrossRefPubMed
3.
Hotchkiss RS, Nicholson DW (2006) Apoptosis and caspases regulate death and inflammation in sepsis. Nat Rev Immunol 6:813–822CrossRefPubMed
4.
5.
Volk HD, Reinke P, Docke WD (2000) Clinical aspects: from systemic inflammation to ‘immunoparalysis’. Chem Immunol 74:162–177CrossRefPubMed
6.
7.
Beutler B, Jiang Z, Georgel P, Crozat K, Croker B, Rutschmann S, Du X, Hoebe K (2006) Genetic analysis of host resistance: toll-like receptor signaling and immunity at large. Annu Rev Immunol 24:353–389CrossRefPubMed
8.
Liew FY, Xu D, Brint EK, O’Neill LA (2005) Negative regulation of toll-like receptor-mediated immune responses. Nat Rev Immunol 5:446–458CrossRefPubMed
9.
Deng JC, Cheng G, Newstead MW, Zeng X, Kobayashi K, Flavell RA, Standiford TJ (2006) Sepsis-induced suppression of lung innate immunity is mediated by IRAK-M. J Clin Invest 116:2532–2542PubMed
10.
Brint EK, Xu D, Liu H, Dunne A, McKenzie AN, O’Neill LA, Liew FY (2004) ST2 is an inhibitor of interleukin 1 receptor and toll-like receptor 4 signaling and maintains endotoxin tolerance. Nat Immunol 5:373–379CrossRefPubMed
11.
Xu D, Chan WL, Leung BP, Huang F, Wheeler R, Piedrafita D, Robinson JH, Liew FY (1998) Selective expression of a stable cell surface molecule on type 2 but not type 1 helper T cells. J Exp Med 187:787–794CrossRefPubMed
12.
Moritz DR, Rodewald HR, Gheyselinck J, Klemenz R (1998) The IL-1 receptor-related T1 antigen is expressed on immature and mature mast cells and on fetal blood mast cell progenitors. J Immunol 161:4866–4874PubMed
13.
Oshikawa K, Yanagisawa K, Tominaga S, Sugiyama Y (2002) ST2 protein induced by inflammatory stimuli can modulate acute lung inflammation. Biochem Biophys Res Commun 299:18–24CrossRefPubMed
14.
Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, McClanahan TK, Zurawski G, Moshrefi M, Qin J, Li X, Gorman DM, Bazan JF, Kastelein RA (2005) IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity 23:479–490CrossRefPubMed
15.
Bergers G, Reikerstorfer A, Braselmann S, Graninger P, Busslinger M (1994) Alternative promoter usage of the Fos-responsive gene Fit-1 generates mRNA isoforms coding for either secreted or membrane-bound proteins related to the IL-1 receptor. EMBO J 13:1176–1188PubMed
16.
Hayakawa H, Hayakawa M, Kume A, Tominaga S (2007) Soluble ST2 blocks interleukin-33 signaling in allergic airway inflammation. J Biol Chem 282:26369–26380CrossRefPubMed
17.
Sanada S, Hakuno D, Higgins LJ, Schreiter ER, McKenzie AN, Lee RT (2007) IL-33 and ST2 comprise a critical biomechanically induced and cardioprotective signaling system. J Clin Invest 117:1538–1549CrossRefPubMed
18.
Oshikawa K, Kuroiwa K, Tago K, Iwahana H, Yanagisawa K, Ohno S, Tominaga SI, Sugiyama Y (2001) Elevated soluble ST2 protein levels in sera of patients with asthma with an acute exacerbation. Am J Respir Crit Care Med 164:277–281PubMed
19.
Tajima S, Oshikawa K, Tominaga S, Sugiyama Y (2003) The increase in serum soluble ST2 protein upon acute exacerbation of idiopathic pulmonary fibrosis. Chest 124:1206–1214CrossRefPubMed
20.
Kuroiwa K, Arai T, Okazaki H, Minota S, Tominaga S (2001) Identification of human ST2 protein in the sera of patients with autoimmune diseases. Biochem Biophys Res Commun 284:1104–1108CrossRefPubMed
21.
Brunner M, Krenn C, Roth G, Moser B, Dworschak M, Jensen-Jarolim E, Spittler A, Sautner T, Bonaros N, Wolner E, Boltz-Nitulescu G, Ankersmit HJ (2004) Increased levels of soluble ST2 protein and IgG1 production in patients with sepsis and trauma. Intensive Care Med 30:1468–1473CrossRefPubMed
22.
Weinberg EO, Shimpo M, De Keulenaer GW, MacGillivray C, Tominaga S, Solomon SD, Rouleau JL, Lee RT (2002) Expression and regulation of ST2, an interleukin-1 receptor family member, in cardiomyocytes and myocardial infarction. Circulation 106:2961–2966CrossRefPubMed
23.
Shimpo M, Morrow DA, Weinberg EO, Sabatine MS, Murphy SA, Antman EM, Lee RT (2004) Serum levels of the interleukin-1 receptor family member ST2 predict mortality and clinical outcome in acute myocardial infarction. Circulation 109:2186–2190CrossRefPubMed
24.
Yin H, Huang BJ, Yang H, Huang YF, Xiong P, Zheng F, Chen XP, Chen YF, Gong FL (2006) Pretreatment with soluble ST2 reduces warm hepatic ischemia/reperfusion injury. Biochem Biophys Res Commun 351:940–946CrossRefPubMed
25.
Fagundes CT, Amaral FA, Souza AL, Vieira AT, Xu D, Liew FY, Souza DG, Teixeira MM (2007) ST2, an IL-1R family member, attenuates inflammation and lethality after intestinal ischemia and reperfusion. J Leukoc Biol 81:492–499CrossRefPubMed
26.
Lohning M, Stroehmann A, Coyle AJ, Grogan JL, Lin S, Gutierrez-Ramos JC, Levinson D, Radbruch A, Kamradt T (1998) T1/ST2 is preferentially expressed on murine Th2 cells, independent of interleukin 4, interleukin 5, and interleukin 10, and important for Th2 effector function. Proc Natl Acad Sci USA 95:6930–6935CrossRefPubMed
27.
Oshikawa K, Yanagisawa K, Tominaga S, Sugiyama Y (2002) Expression and function of the ST2 gene in a murine model of allergic airway inflammation. Clin Exp Allergy 32:1520–1526CrossRefPubMed
28.
Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G (2003) 2001 SCCM/ESICM/ACCP/ATS/SIS international sepsis definitions conference. Crit Care Med 31:1250–1256CrossRefPubMed
29.
Dellinger RP, Carlet JM, Gerlach H, Ramsey G, Levy M (2004) The surviving sepsis guidelines: not another “groundhog day”. Crit Care Med 32:1601–1602CrossRefPubMed
30.
van Zoelen MA, Laterre PF, van Veen SQ, van Till JW, Wittebole X, Bresser P, Tanck MW, Dugernier T, Ishizaka A, Boermeester MA, van der Poll T (2007) Systemic and local high mobility group box 1 concentrations during severe infection. Crit Care Med 35:2799–2804CrossRefPubMed
31.
(1992) 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 20:864–874
32.
Becerra A, Warke RV, de Bosch N, Rothman AL, Bosch I (2008) Elevated levels of soluble ST2 protein in dengue virus infected patients. Cytokine 41:114–120CrossRefPubMed
33.
Weinberg EO, Shimpo M, Hurwitz S, Tominaga S, Rouleau JL, Lee RT (2003) Identification of serum soluble ST2 receptor as a novel heart failure biomarker. Circulation 107:721–726CrossRefPubMed
34.
Calandra T, Gerain J, Heumann D, Baumgartner JD, Glauser MP (1991) High circulating levels of interleukin-6 in patients with septic shock: evolution during sepsis, prognostic value, and interplay with other cytokines. The Swiss–Dutch J5 immunoglobulin study group. Am J Med 91:23–29CrossRefPubMed
35.
Casey LC, Balk RA, Bone RC (1993) Plasma cytokine and endotoxin levels correlate with survival in patients with the sepsis syndrome. Ann Intern Med 119:771–778PubMed
36.
Damas P, Reuter A, Gysen P, Demonty J, Lamy M, Franchimont P (1989) Tumor necrosis factor and interleukin-1 serum levels during severe sepsis in humans. Crit Care Med 17:975–978CrossRefPubMed
37.
Marks JD, Marks CB, Luce JM, Montgomery AB, Turner J, Metz CA, Murray JF (1990) Plasma tumor necrosis factor in patients with septic shock. Mortality rate, incidence of adult respiratory distress syndrome, and effects of methylprednisolone administration. Am Rev Respir Dis 141:94–97PubMed
38.
Pinsky MR, Vincent JL, Deviere J, Alegre M, Kahn RJ, Dupont E (1993) Serum cytokine levels in human septic shock. Relation to multiple-system organ failure and mortality. Chest 103:565–575CrossRefPubMed
39.
Metadata
Title
Soluble ST2 plasma concentrations predict mortality in severe sepsis
Authors
Jacobien J. Hoogerwerf
Michael W. T. Tanck
Marieke A. D. van Zoelen
Xavier Wittebole
Pierre-François Laterre
Tom van der Poll
Publication date
01-04-2010
Publisher
Springer-Verlag
Published in
Intensive Care Medicine / Issue 4/2010
Print ISSN: 0342-4642
Electronic ISSN: 1432-1238
DOI
https://doi.org/10.1007/s00134-010-1773-0

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