Journal Article

Regulation of YKL-40 expression by corticosteroids: effect on pro-inflammatory macrophages in vitro and its modulation in COPD in vivo

Sterk, P. J., Kunz, L. I. Z., van’t Wout, E. F. A., Kerstjens, H. A. M., van Schadewijk, A., Postma, D. S., Hiemstra, P. S.

2015

Overview

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. Trial registration ClinicalTrials.gov, registration number: NCT00158847

• Publisher: BioMed Central,BioMed Central Ltd,Nature Publishing Group
• Subject: Adipokines - blood / Adipokines - genetics / Adipokines - metabolism / Administration, Inhalation / Aged / Analysis / Anti-Inflammatory Agents - administration & dosage / Anti-Inflammatory Agents - pharmacology / Biomarkers - metabolism / Bronchodilator Agents - administration & dosage / Care and treatment / Cells, Cultured / Chitinase-3-Like Protein 1 / Complications and side effects / Corticoids / Dexamethasone / Dexamethasone - pharmacology / Dose-Response Relationship, Drug / Down-Regulation / Drug Administration Schedule / Female / Fluticasone-Salmeterol Drug Combination - administration & dosage / Gene expression / Glucocorticoids - administration & dosage / Glucocorticoids - pharmacology / Health aspects / Humans / Inflammation Mediators - metabolism / Inflammation Mediators - pharmacology / Influence / Lectins - blood / Lectins - genetics / Lectins - metabolism / Lung diseases, Obstructive / Macrophages / Macrophages - drug effects / Macrophages - immunology / Macrophages - metabolism / Male / Medicine / Medicine & Public Health / Middle Aged / Netherlands / Phenotype / Pneumology/Respiratory System / Pulmonary Disease, Chronic Obstructive - blood / Pulmonary Disease, Chronic Obstructive - diagnosis / Pulmonary Disease, Chronic Obstructive - drug therapy / Pulmonary Disease, Chronic Obstructive - genetics / Pulmonary Disease, Chronic Obstructive - immunology / Sputum - metabolism / Time Factors / Treatment Outcome