title: Novel insights in the regulation of CCL18 secretion by monocytes and dendritic cells via cytokines, toll-like receptors and rheumatoid synovial fluid.
abstract: BACKGROUND
  The T cell attracting chemokine CCL18 is produced by antigen presenting cells and a role for CCL18 has been suggested in the pathogenesis of a variety of diseases. Rheumatoid arthritis (RA) is one of these conditions, in which abundant CCL18 production is present. Although Th2 cytokines and IL-10 are known to have an effect on CCL18 production, there are several gaps in our knowledge regarding the exact regulation of CCL18 secretion, both in general and in RA. In this study we provide new insights in the regulation of CCL18 secretion by monocytes and dendritic cells.
  
  
  RESULTS
  In contrast to a large panel of pro-inflammatory stimuli (IL-1beta, TNF-alpha, IL-10, IL-13, IL-15, IL-17, IL-18, IFN-gamma), T cell mimicking molecules (RANKL, CD40L) or TLR driven maturation, the anti-inflammatory IL-10 strongly stimulated DC to secrete CCL18. On freshly isolated monocytes, CCL18 secretion was induced by IL-4 and IL-13, in strong synergy with IL-10. This synergistic effect could already be observed after only 24 hours, indicating that not only macrophages and dendritic cells, but also monocytes secrete CCL18 under these stimulatory conditions. A high CCL18 expression was detected in RA synovial tissue and incubation of monocytes with synovial fluid from RA patients clearly enhanced the effects of IL-4, IL-13 and IL-10. Surprisingly, the effect of synovial fluid was not driven by IL-10 of IL-13, suggesting the presence of another CCL18 inducing factor in synovial fluid.
  
  
  CONCLUSIONS
  In summary, IL-10 synergistically induces CCL18 secretion in combination with IL-4 of IL-13 on monocytes and monocyte derived cells. The effects of IL-14, IL-13 and IL-10 are strongly enhanced by synovial fluid. This synergy may contribute to the high CCL18 expression in RA.
authors.affiliation: Department of Rheumatology, Radboud University Nijmegen Medical Centre, The Netherlands. a.vanlieshout@reuma.umcn.nl
authors.forename: Antoine W T
authors.initials: AW
authors.lastname: van Lieshout
authors.forename: Robbert
authors.initials: R
authors.lastname: van der Voort
authors.forename: Linda M P
authors.initials: LM
authors.lastname: le Blanc
authors.forename: Mieke F
authors.initials: MF
authors.lastname: Roelofs
authors.forename: B Willem
authors.initials: BW
authors.lastname: Schreurs
authors.forename: Piet L C M
authors.initials: PL
authors.lastname: van Riel
authors.forename: Gosse J
authors.initials: GJ
authors.lastname: Adema
authors.forename: Timothy R D J
authors.initials: TR
authors.lastname: Radstake
mesh_terms: D001172:Arthritis, Rheumatoid / Q000276:immunology*; D002478:Cells, Cultured; D019742:Chemokines, CC / Q000096:biosynthesis*; D016207:Cytokines / Q000494:pharmacology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D004357:Drug Synergism; D006801:Humans; D016753:Interleukin-10 / Q000494:pharmacology; D018793:Interleukin-13 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D007378:Interleukins / Q000494:pharmacology*; D009000:Monocytes / Q000187:drug effects / Q000276:immunology*; D013582:Synovial Fluid / Q000276:immunology*; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: C111792:CCL18 protein, human; D019742:Chemokines, CC; D016207:Cytokines; D018793:Interleukin-13; D007378:Interleukins; D051193:Toll-Like Receptors; D016753:Interleukin-10; D015847:Interleukin-4