title: The discriminative capacity of soluble Toll-like receptor (sTLR)2 and sTLR4 in inflammatory diseases.
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 (rs = 0.80, P < 0.05), IL-6 (rs = 0.65, P < 0.05), and IL-1Ra (rs = 0.57, P = 0.06), and negatively with IL-10 (rs = -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.
authors.forename: Jaap
authors.initials: J
authors.lastname: Ten Oever
authors.forename: Matthijs
authors.initials: M
authors.lastname: Kox
authors.forename: Frank L
authors.initials: FL
authors.lastname: van de Veerdonk
authors.forename: Khutso M
authors.initials: KM
authors.lastname: Mothapo
authors.forename: Adriana
authors.initials: A
authors.lastname: Slavcovici
authors.forename: Tim L
authors.initials: TL
authors.lastname: Jansen
authors.forename: Lieke
authors.initials: L
authors.lastname: Tweehuysen
authors.forename: Evangelos J
authors.initials: EJ
authors.lastname: Giamarellos-Bourboulis
authors.forename: Peter M
authors.initials: PM
authors.lastname: Schneeberger
authors.forename: Peter C
authors.initials: PC
authors.lastname: Wever
authors.forename: Monique
authors.initials: M
authors.lastname: Stoffels
authors.forename: Anna
authors.initials: A
authors.lastname: Simon
authors.forename: Jos W M
authors.initials: JW
authors.lastname: van der Meer
authors.forename: Melissa D
authors.initials: MD
authors.lastname: Johnson
authors.forename: Bart-Jan
authors.initials: BJ
authors.lastname: Kullberg
authors.forename: Peter
authors.initials: P
authors.lastname: Pickkers
authors.forename: Alexandre
authors.initials: A
authors.lastname: Pachot
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D002097:C-Reactive Protein / Q000378:metabolism; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D003710:Demography; D005260:Female; D006801:Humans; D007249:Inflammation / Q000097:blood*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D012372:ROC Curve; D012995:Solubility; D051195:Toll-Like Receptor 2 / Q000097:blood*; D051197:Toll-Like Receptor 4 / Q000097:blood*; D055815:Young Adult
chemical_list: D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D002097:C-Reactive Protein