Top

Published in:

Open Access 01-12-2014 | Research article

The discriminative capacity of soluble Toll-like receptor (sTLR)2 and sTLR4 in inflammatory diseases

Authors: Jaap ten Oever, Matthijs Kox, Frank L van de Veerdonk, Khutso M Mothapo, Adriana Slavcovici, Tim L Jansen, Lieke Tweehuysen, Evangelos J Giamarellos-Bourboulis, Peter M Schneeberger, Peter C Wever, Monique Stoffels, Anna Simon, Jos WM van der Meer, Melissa D Johnson, Bart-Jan Kullberg, Peter Pickkers, Alexandre Pachot, Leo AB Joosten, Mihai G Netea

Published in: BMC Immunology | Issue 1/2014

Abstract

Background

The extracellular domains of cytokine receptors are released during inflammation, but little is known about the shedding of Toll-like receptors (TLR) and whether they can be used as diagnostic biomarkers.

Methods

The release of sTLR2 and sTLR4 was studied in in-vitro stimulations, as well as in-vivo during experimental human endotoxemia (n = 11, 2 ng/kg LPS), and in plasma of 394 patients with infections (infectious mononucleosis, measles, respiratory tract infections, bacterial sepsis and candidemia) or non-infectious inflammation (Crohn’s disease, gout, rheumatoid arthritis, autoinflammatory syndromes and pancreatitis). Using C-statistics, the value of sTLR2 and sTLR4 levels for discrimination between infections and non-infectious inflammatory diseases, as well as between viral and bacterial infections was analyzed.

Results

In-vitro, peripheral blood mononuclear cells released sTLR2 and sTLR4 by exposure to microbial ligands. During experimental human endotoxemia, plasma concentrations peaked after 2 hours (sTLR4) and 4 hours (sTLR2). sTLR4 did not correlate with cytokines, but sTLR2 correlated positively with TNFα (r_s = 0.80, P < 0.05), IL-6 (r_s = 0.65, P < 0.05), and IL-1Ra (r_s = 0.57, P = 0.06), and negatively with IL-10 (r_s = -0.58, P = 0.06), respectively. sTLR4 had a similar area under the ROC curve [AUC] for differentiating infectious and non-infectious inflammation compared to CRP: 0.72 (95% CI 0.66-0.79) versus 0.74 (95% CI 0.69-0.80) [P = 0.80], while sTLR2 had a lower AUC: 0.60 (95% CI 0.54-0.66) [P = 0.0004]. CRP differentiated bacterial infections better from viral infections than sTLR2 and sTLR4: AUC 0.94 (95% CI 0.90-0.96) versus 0.58 (95% CI 0.51-0.64) and 0.75 (95% CI 0.70-0.80), respectively [P < 0.0001 for both].

Conclusions

sTLRs are released into the circulation, and suggest the possibility to use sTLRs as diagnostic tool in inflammatory conditions.

Available only for authorised users

Liew FY, Xu D, Brint EK, O’Neill LA: Negative regulation of toll-like receptor-mediated immune responses. Nat Rev Immunol. 2005, 5: 446-458. 10.1038/nri1630.PubMedCrossRef

Cook DN, Pisetsky DS, Schwartz DA: Toll-like receptors in the pathogenesis of human disease. Nat Immunol. 2004, 5: 975-979. 10.1038/ni1116.PubMedCrossRef

Heaney ML, Golde DW: Soluble cytokine receptors. Blood. 1996, 87: 847-857.PubMed

LeBouder E, Rey-Nores JE, Rushmere NK, Grigorov M, Lawn SD, Affolter M, Griffin GE, Ferrara P, Schiffrin EJ, Morgan BP, Labeta MO: Soluble forms of Toll-like receptor (TLR)2 capable of modulating TLR2 signaling are present in human plasma and breast milk. J Immunol. 2003, 171: 6680-6689. 10.4049/jimmunol.171.12.6680.PubMedCrossRef

Iwami KI, Matsuguchi T, Masuda A, Kikuchi T, Musikacharoen T, Yoshikai Y: Cutting edge: naturally occurring soluble form of mouse Toll-like receptor 4 inhibits lipopolysaccharide signaling. J Immunol. 2000, 165: 6682-6686. 10.4049/jimmunol.165.12.6682.PubMedCrossRef

Dulay AT, Buhimschi CS, Zhao G, Oliver EA, Mbele A, Jing S, Buhimschi IA: Soluble TLR2 is present in human amniotic fluid and modulates the intraamniotic inflammatory response to infection. J Immunol. 2009, 182: 7244-7253. 10.4049/jimmunol.0803517.PubMedCrossRef

Kuroishi T, Tanaka Y, Sakai A, Sugawara Y, Komine K, Sugawara S: Human parotid saliva contains soluble toll-like receptor (TLR) 2 and modulates TLR2-mediated interleukin-8 production by monocytic cells. Mol Immunol. 2007, 44: 1969-1976. 10.1016/j.molimm.2006.09.028.PubMedCrossRef

Yang HB, Xie KQ, Deng JM, Qin SM: Expression of soluble Toll-like receptors in pleural effusions. Chin Med J (Engl). 2010, 123: 2225-2230.

Kacerovsky M, Andrys C, Drahosova M, Musilova I, Hornychova H, Lesko D, Tosner J, Jacobsson B: Soluble Toll-like receptor 1 family members in the amniotic fluid of women with preterm prelabor rupture of the membranes. J Matern Fetal Neonatal Med. 2012, 25: 1699-1704. 10.3109/14767058.2012.658463.PubMedCrossRef

10.

Kacerovsky M, Andrys C, Hornychova H, Pliskova L, Lancz K, Musilova I, Drahosova M, Bolehovska R, Tambor V, Jacobsson B: Amniotic fluid soluble Toll-like receptor 4 in pregnancies complicated by preterm prelabor rupture of the membranes. J Matern Fetal Neonatal Med. 2012, 25: 1148-1155. 10.3109/14767058.2011.626821.PubMedCrossRef

11.

Ubenauf KM, Krueger M, Henneke P, Berner R: Lipopolysaccharide binding protein is a potential marker for invasive bacterial infections in children. Pediatr Infect Dis J. 2007, 26: 159-162. 10.1097/01.inf.0000253064.88722.6d.PubMedCrossRef

12.

Chalupa P, Beran O, Herwald H, Kasprikova N, Holub M: Evaluation of potential biomarkers for the discrimination of bacterial and viral infections. Infection. 2011, 39: 411-417. 10.1007/s15010-011-0126-4.PubMedCrossRef

13.

Andrys C, Kacerovsky M, Drahosova M, Musilova I, Pliskova L, Hornychova H, Prochazka M, Jacobsson B: Amniotic fluid soluble Toll-like receptor 2 in pregnancies complicated by preterm prelabor rupture of membranes. J Matern Fetal Neonatal Med. 2013, 26: 520-527. 10.3109/14767058.2012.741634.PubMedCrossRef

14.

Kox M, de Kleijn S, Pompe JC, Ramakers BP, Netea MG, van der Hoeven JG, Hoedemaekers CW, Pickkers P: Differential ex vivo and in vivo endotoxin tolerance kinetics following human endotoxemia. Crit Care Med. 2011, 39: 1866-1870. 10.1097/CCM.0b013e3182190d5d.PubMedCrossRef

15.

ten Oever J, Riza A, Sabou M, Cismaru C, Netea MG, Slavcovici A: Characterization of the acute inflammatory response in measles infection. J Ped Infect Dis. 2014, 3: 197-200.CrossRef

16.

van de Veerdonk FL, Wever PC, Hermans MH, Fijnheer R, Joosten LA, van der Meer JW, Netea MG, Schneeberger PM: IL-18 serum concentration is markedly elevated in acute EBV infection and can serve as a marker for disease severity. J Infect Dis. 2012, 206: 197-201. 10.1093/infdis/jis335.PubMedCrossRef

17.

Giamarellos-Bourboulis EJ, Tsangaris I, Kanni T, Mouktaroudi M, Pantelidou I, Adamis G, Atmatzidis S, Chrisofos M, Evangelopoulou V, Frantzeskaki F, Giannopoulos P, Giannikopoulos G, Gialvalis D, Gourgoulis GM, Kotzampassi K, Katsifa K, Kofinas G, Kontopidou F, Koratzanis G, Koulouras V, Koutsikou A, Koupetori M, Kritselis I, Leonidou L, Mega A, Mylona V, Nikolaou H, Orfanos S, Panagopoulos P, Paramythiotou E, et al.: Procalcitonin as an early indicator of outcome in sepsis: a prospective observational study. J Hosp Infect. 2011, 77: 58-63. 10.1016/j.jhin.2010.07.026.PubMedCrossRef

18.

Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G: 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med. 2003, 31: 1250-1256. 10.1097/01.CCM.0000050454.01978.3B.PubMedCrossRef

19.

Johnson MD, Plantinga TS, van de Vosse E, Velez Edwards DR, Smith PB, Alexander BD, Yang JC, Kremer D, Laird GM, Oosting M, Joosten LA, van der Meer JW, van Dissel JT, Walsh TJ, Perfect JR, Kullberg BJ, Scott WK, Netea MG: Cytokine gene polymorphisms and the outcome of invasive candidiasis: a prospective cohort study. Clin Infect Dis. 2012, 54: 502-510. 10.1093/cid/cir827.PubMedPubMedCentralCrossRef

20.

Mylona V, Koussoulas V, Tzivras D, Makrygiannis E, Georgopoulou P, Koratzanis G, Giamarellos-Bourboulis EJ, Tzivras MD: Changes in adaptive and innate immunity in patients with acute pancreatitis and systemic inflammatory response syndrome. Pancreatology. 2011, 11: 475-481. 10.1159/000329460.PubMedCrossRef

21.

Prevoo ML, van’t Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL: Modified disease activity scores that include twenty-eight-joint counts: Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum. 1995, 38: 44-48. 10.1002/art.1780380107.PubMedCrossRef

22.

DeLong ER, DeLong DM, Clarke-Pearson DL: Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics. 1988, 44: 837-845. 10.2307/2531595.PubMedCrossRef

23.

Zunt SL, Burton LV, Goldblatt LI, Dobbins EE, Srinivasan M: Soluble forms of Toll-like receptor 4 are present in human saliva and modulate tumour necrosis factor-alpha secretion by macrophage-like cells. Clin Exp Immunol. 2009, 156: 285-293. 10.1111/j.1365-2249.2009.03854.x.PubMedPubMedCentralCrossRef

24.

Raby AC, Le Bouder E, Colmont C, Davies J, Richards P, Coles B, George CH, Jones SA, Brennan P, Topley N, Labeta MO: Soluble TLR2 reduces inflammation without compromising bacterial clearance by disrupting TLR2 triggering. J Immunol. 2009, 183: 506-517. 10.4049/jimmunol.0802909.PubMedCrossRef

25.

Hyakushima N, Mitsuzawa H, Nishitani C, Sano H, Kuronuma K, Konishi M, Himi T, Miyake K, Kuroki Y: Interaction of soluble form of recombinant extracellular TLR4 domain with MD-2 enables lipopolysaccharide binding and attenuates TLR4-mediated signaling. J Immunol. 2004, 173: 6949-6954. 10.4049/jimmunol.173.11.6949.PubMedCrossRef

26.

Tye H, Kennedy CL, Najdovska M, McLeod L, McCormack W, Hughes N, Dev A, Sievert W, Ooi CH, Ishikawa TO, Oshima H, Bhathal PS, Parker AE, Oshima M, Tan P, Jenkins BJ: STAT3-driven upregulation of TLR2 promotes gastric tumorigenesis independent of tumor inflammation. Cancer Cell. 2012, 22: 466-478. 10.1016/j.ccr.2012.08.010.PubMedCrossRef

27.

Marsik C, Mayr F, Cardona F, Derhaschnig U, Wagner OF, Jilma B: Endotoxaemia modulates Toll-like receptors on leucocytes in humans. Br J Haematol. 2003, 121: 653-656. 10.1046/j.1365-2141.2003.04350.x.PubMedCrossRef

28.

Cognasse F, Hamzeh H, Chavarin P, Acquart S, Genin C, Garraud O: Evidence of Toll-like receptor molecules on human platelets. Immunol Cell Biol. 2005, 83: 196-198. 10.1111/j.1440-1711.2005.01314.x.PubMedCrossRef

29.

Hayashi F, Means TK, Luster AD: Toll-like receptors stimulate human neutrophil function. Blood. 2003, 102: 2660-2669. 10.1182/blood-2003-04-1078.PubMedCrossRef

30.

McGettrick AF, O’Neill LA: Localisation and trafficking of Toll-like receptors: an important mode of regulation. Curr Opin Immunol. 2010, 22: 20-27. 10.1016/j.coi.2009.12.002.PubMedCrossRef

31.

Gazi U, Rosas M, Singh S, Heinsbroek S, Haq I, Johnson S, Brown GD, Williams DL, Taylor PR, Martinez-Pomares L: Fungal recognition enhances mannose receptor shedding through dectin-1 engagement. J Biol Chem. 2011, 286: 7822-7829. 10.1074/jbc.M110.185025.PubMedPubMedCentralCrossRef

Title: The discriminative capacity of soluble Toll-like receptor (sTLR)2 and sTLR4 in inflammatory diseases
Authors: Jaap ten Oever
Matthijs Kox
Frank L van de Veerdonk
Khutso M Mothapo
Adriana Slavcovici
Tim L Jansen
Lieke Tweehuysen
Evangelos J Giamarellos-Bourboulis
Peter M Schneeberger
Peter C Wever
Monique Stoffels
Anna Simon
Jos WM van der Meer
Melissa D Johnson
Bart-Jan Kullberg
Peter Pickkers
Alexandre Pachot
Leo AB Joosten
Mihai G Netea
Publication date: 01-12-2014
Publisher: BioMed Central
Published in: BMC Immunology / Issue 1/2014
Electronic ISSN: 1471-2172
DOI: https://doi.org/10.1186/s12865-014-0055-y

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

The discriminative capacity of soluble Toll-like receptor (sTLR)2 and sTLR4 in inflammatory diseases

Abstract

Background

Methods

Results

Conclusions

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2014

Capturing needles in haystacks: a comparison of B-cell receptor sequencing methods

High CD56++CD16- natural killer (NK) cells among suboptimal immune responders after four years of suppressive antiretroviral therapy in an African adult HIV treatment cohort

Transcriptional profiling of the spleen in progressive visceral leishmaniasis reveals mixed expression of type 1 and type 2 cytokine-responsive genes

Continuous retinoic acid induces the differentiation of mature regulatory monocytes but fails to induce regulatory dendritic cells

Mannose-binding lectin gene variants and infections in patients receiving autologous stem cell transplantation

ImmunoGlobulin galaxy (IGGalaxy) for simple determination and quantitation of immunoglobulin heavy chain rearrangements from NGS

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page