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-(M1) and anti-inflammatory (M2) 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 M1 and M2, 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 M1 and M2, respectively) and stimulated for 24 h with LPS, TNFα, or oncostatin M (OSM). M1 and M2 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 M1 cells secreted significantly more YKL-40 than M2, 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 M1. 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 M1 cells is higher than from M2 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 M1, 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 M1 macrophages in vitro, but not for monitoring the effect of ICS in COPD. Trial registration: ClinicalTrials.gov, registration number: NCT00158847