title: Regulation of YKL-40 expression by corticosteroids: effect on pro-inflammatory macrophages in vitro and its modulation in COPD in vivo.
abstract: BACKGROUND
  Macrophages constitute a heterogeneous cell population with pro- (MΦ1) and anti-inflammatory (MΦ2) cells. The soluble chitinase-like-protein YKL-40 is expressed in macrophages and various other cell types, and has been linked to a variety of inflammatory diseases, including COPD. Dexamethasone strongly reduces YKL-40 expression in peripheral blood mononuclear cells (PBMC) in vitro. We hypothesized that: a) YKL-40 is differentially expressed by MΦ1 and MΦ2, b) is decreased by corticosteroids and c) that long-term treatment with inhaled corticosteroids (ICS) affects YKL-40 levels in serum and sputum of COPD patients.
  
  
  METHODS
  Monocytes of healthy subjects were cultured in vitro for 7 days with either GM-CSF or M-CSF (for MΦ1 and MΦ2, respectively) and stimulated for 24 h with LPS, TNFα, or oncostatin M (OSM). MΦ1 and MΦ2 differentiation was assessed by measuring secretion of IL-12p40 and IL-10, respectively. YKL-40 expression in macrophages was measured by quantitative RT-PCR (qPCR) and ELISA; serum and sputum YKL-40 levels were analyzed by ELISA.
  
  
  RESULTS
  Pro-inflammatory MΦ1 cells secreted significantly more YKL-40 than MΦ2, which was independent of stimulation with LPS, TNFα or OSM (p < 0.001) and confirmed by qPCR. Dexamethasone dose-dependently and significantly inhibited YKL-40 protein and mRNA levels in MΦ1. Serum YKL-40 levels of COPD patients were significantly higher than sputum YKL-40 levels but were not significantly changed by ICS treatment.
  
  
  CONCLUSIONS
  YKL-40 secretion from MΦ1 cells is higher than from MΦ2 cells and is unaffected by further stimulation with pro-inflammatory agents. Furthermore, YKL-40 release from cultured monocyte-derived macrophages is inhibited by dexamethasone especially in MΦ1, but ICS treatment did not change YKL-40 serum and sputum levels in COPD. These results indicate that YKL-40 expression could be used as a marker for MΦ1 macrophages in vitro, but not for monitoring the effect of ICS in COPD.
  
  
  BACKGROUND
  ClinicalTrials.gov, registration number: NCT00158847.
authors.affiliation: Department of Pulmonology, Leiden University Medical Center, Albinusdreef 2, NL-2333, ZA, Leiden, The Netherlands. L.I.Z.Kunz@lumc.nl.
authors.forename: L I Z
authors.initials: LI
authors.lastname: Kunz
authors.affiliation: Department of Pulmonology, Leiden University Medical Center, Albinusdreef 2, NL-2333, ZA, Leiden, The Netherlands. E.F.A.van_t_Wout@lumc.nl.
authors.forename: E F A
authors.initials: EF
authors.lastname: van't Wout
authors.affiliation: Department of Pulmonology, Leiden University Medical Center, Albinusdreef 2, NL-2333, ZA, Leiden, The Netherlands. A.van_Schadewijk@lumc.nl.
authors.forename: A
authors.initials: A
authors.lastname: van Schadewijk
authors.affiliation: Department of Pulmonology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. D.S.Postma@umcg.nl.
authors.forename: D S
authors.initials: DS
authors.lastname: Postma
authors.affiliation: Department of Pulmonology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. H.A.M.Kerstjens@umcg.nl.
authors.forename: H A M
authors.initials: HA
authors.lastname: Kerstjens
authors.affiliation: Department of Respiratory Medicine, Academic Medical Center, Amsterdam, The Netherlands. P.J.Sterk@amc.nl.
authors.forename: P J
authors.initials: PJ
authors.lastname: Sterk
authors.affiliation: Department of Pulmonology, Leiden University Medical Center, Albinusdreef 2, NL-2333, ZA, Leiden, The Netherlands. P.S.Hiemstra@lumc.nl.
authors.forename: P S
authors.initials: PS
authors.lastname: Hiemstra
mesh_terms: D054392:Adipokines / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D000280:Administration, Inhalation; D000368:Aged; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology*; D015415:Biomarkers / Q000378:metabolism; D001993:Bronchodilator Agents / Q000008:administration & dosage; D002478:Cells, Cultured; D000071451:Chitinase-3-Like Protein 1; D003907:Dexamethasone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004334:Drug Administration Schedule; D005260:Female; D000068297:Fluticasone-Salmeterol Drug Combination / Q000008:administration & dosage; D005938:Glucocorticoids / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism / Q000494:pharmacology; D037102:Lectins / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D010641:Phenotype; D029424:Pulmonary Disease, Chronic Obstructive / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D013183:Sputum / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D054392:Adipokines; D000893:Anti-Inflammatory Agents; D015415:Biomarkers; D001993:Bronchodilator Agents; C084533:CHI3L1 protein, human; D000071451:Chitinase-3-Like Protein 1; D000068297:Fluticasone-Salmeterol Drug Combination; D005938:Glucocorticoids; D018836:Inflammation Mediators; D037102:Lectins; D003907:Dexamethasone