Author(s):
|
Oever, J. ten
;
Kox, M.
;
Veerdonk, F.L. van de
;
Mothapo, K.M.
; Slavcovici, A.; Jansen, T.L.Th.A.; Tweehuysen, L.;
Giamarellos-Bourboulis, E.J.
; Schneeberger, P.M.; Wever, P.C.;
Stoffels, M.
;
Simon, A.
;
Meer, J.W.M. van der
; Johnson, M.D.;
Kullberg, B.J.
;
Pickkers, P.
; Pachot, A.;
Joosten, L.A.
;
Netea, M.G.
|
Subject:
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Radboudumc 4: lnfectious Diseases and Global Health RIHS: Radboud Institute for Health Sciences Radboudumc 4: lnfectious Diseases and Global Health RIMLS: Radboud Institute for Molecular Life Sciences Radboudumc 5: Inflammatory diseases RIMLS: Radboud Institute for Molecular Life Sciences |
Organization:
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Internal Medicine Intensive Care Rheumatology |
Abstract:
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BackgroundThe 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.MethodsThe release of sTLR2 and sTLR4 was studied in in-vitro stimulations, as well as in-vivo during experimental human endotoxemia (n inverted question mark= inverted question mark11, 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 inverted question marks 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.ResultsIn-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 TNF inverted question mark (rs inverted question mark= inverted question mark0.80, P inverted question mark< inverted question mark0.05), IL-6 (rs inverted question mark= inverted question mark0.65, P inverted question mark< inverted question mark0.05), and IL-1Ra (rs inverted question mark= inverted question mark0.57, P inverted question mark= inverted question mark0.06), and negatively with IL-10 (rs inverted question mark= inverted question mark-0.58, P inverted question mark= inverted question mark0.06), 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 inverted question mark= inverted question mark0.80], while sTLR2 had a lower AUC: 0.60 (95% CI 0.54-0.66) [P inverted question mark= inverted question mark0.0004]. 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 inverted question mark< inverted question mark0.0001 for both].ConclusionssTLRs are released into the circulation, and suggest the possibility to use sTLRs as diagnostic tool in inflammatory conditions.
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