title: Enhanced interleukin-10 production by dendritic cells upon stimulation with Toll-like receptor 4 agonists in systemic sclerosis that is possibly implicated in CCL18 secretion.
abstract: BACKGROUND
  It has been suggested that the T-cell attracting and profibrotic chemokine CCL18 might play a role in the pathogenesis of systemic sclerosis (SSc). However, it is unclear what underlies the higher CCL18 levels in SSc. The aim of our study was to determine whether Toll-like receptor (TLR)-mediated stimulation of monocytes and dendritic cells (DCs) contributes to the higher levels of CCL18 in SSc.
  
  
  METHODS
  CCL18 levels were measured in 40 patients with SSc, primary Raynaud's phenomenon (RP) and healthy controls. The presence of TLR4 agonists in the circulation of SSc patients was investigated using TLR4 transgenic Chinese hamster ovary (CHO) cells. CCL18 and interleukin (IL)-10 secretion by monocytes/macrophages and monocyte-derived DCs (moDCs) was measured in the supernatant. The indirect effect of lipopolysaccharide (LPS)-stimulated moDCs on CCL18 secretion by monocytes/macrophages was investigated using a transwell system.
  
  
  RESULTS
  CCL18 levels were significantly elevated in SSc patients compared to patients with RP and healthy controls. SSc sera strongly induced CD25 expression on CHO cells genetically modified to express TLR4 but not on those expressing CD14 only. By contrast, serum from systemic lupus erythematosus (SLE) patients or healthy individuals did not have an effect. Neither monocytes/macrophages nor moDCs from SSc patients secreted higher levels of CCL18 compared to healthy controls. However, moDCs matured with the TLR4 ligand LPS from patients with SSc did secrete significantly higher amounts of IL-10 compared to those from healthy counterparts, which were IL-10 dependent.
  
  
  CONCLUSIONS
  Our results suggest that elevated CCL18 levels in SSc are not caused by an intrinsically enhanced CCL18 secretion by monocytes/macrophages but are, at least partly, orchestrated by an enhanced IL-10 secretion by TLR4-stimulated DCs. These observations suggest a role for TLR4 ligands and DCs in the pathogenesis of SSc, a topic that warrants further investigation.
authors.affiliation: Department of Rheumatology, Radboud University Nijmegen Medical Centre, the Netherlands.
authors.forename: A W T
authors.initials: AW
authors.lastname: van Lieshout
authors.forename: M C
authors.initials: MC
authors.lastname: Vonk
authors.forename: S J H
authors.initials: SJ
authors.lastname: Bredie
authors.forename: L B A
authors.initials: LB
authors.lastname: Joosten
authors.forename: M G
authors.initials: MG
authors.lastname: Netea
authors.forename: P L C M
authors.initials: PL
authors.lastname: van Riel
authors.forename: R
authors.initials: R
authors.lastname: Lafyatis
authors.forename: F H J
authors.initials: FH
authors.lastname: van den Hoogen
authors.forename: T R D J
authors.initials: TR
authors.lastname: Radstake
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D002478:Cells, Cultured; D019742:Chemokines, CC / Q000235:genetics / Q000378:metabolism*; D006224:Cricetinae; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D005260:Female; D006801:Humans; D016753:Interleukin-10 / Q000276:immunology* / Q000378:metabolism; D008297:Male; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D011336:Probability; D011928:Raynaud Disease / Q000097:blood / Q000276:immunology* / Q000503:physiopathology; D012016:Reference Values; D012595:Scleroderma, Systemic / Q000097:blood / Q000276:immunology* / Q000503:physiopathology; D012680:Sensitivity and Specificity; D018709:Statistics, Nonparametric; D051197:Toll-Like Receptor 4 / Q000819:agonists
chemical_list: D015415:Biomarkers; C111792:CCL18 protein, human; D019742:Chemokines, CC; D016207:Cytokines; D051197:Toll-Like Receptor 4; D016753:Interleukin-10