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

Abstract

BackgroundMacrophages 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.MethodsMonocytes 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.ResultsPro-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.ConclusionsYKL-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 registrationClinicalTrials.gov, registration number: NCT00158847

<p>Chitinases and Chitinase-Like Proteins in Obstructive Lung Diseases – Current Concepts and Potential Applications</p>

“…60 Moreover, an in vitro study by Kunz et al revealed that dexamethasone strongly inhibited the release of YKL-40 from the population of proinflammatory macrophages that are characterized by classic mechanism of activation, secretion of pro-inflammatory cytokines (eg, IFN-γ, IL-1, IL-6, IL-12) and promotion of Th1 immunity. 116 However, long-term treatment with ICS (30 months) did not significantly change sputum and serum YKL-40 levels in patients with COPD. 116 The lack of change in serum YKL-40 level may result from a low circulating corticosteroid level during ICS treatment.…”

“…116 However, long-term treatment with ICS (30 months) did not significantly change sputum and serum YKL-40 levels in patients with COPD. 116 The lack of change in serum YKL-40 level may result from a low circulating corticosteroid level during ICS treatment. 117 In addition, there are data suggesting that lung macrophages from patients with COPD have reduced corticosteroid sensitivity compared with macrophages from smokers without COPD.…”

Mortality prediction in stable hemodialysis patients is refined by YKL-40, a 40-kDa glycoprotein associated with inflammation

“…Concerning the latter, 12, 19, and 33 lethal cardiovascular events occurred in the lower, middle, and upper YKL-40 terciles, respectively. IP-10 terciles showed a moderate correlation with all-cause (35,61, and 73 events per tercile; P < 0.001) and cardiovascular mortality (11,24, and 29 events per tercile; P < 0.008). MCP-1 did not reach significance in any of these categories ( Figure 2, Supplementary Table S4).…”

YKL-39 as a Potential New Target for Anti-Angiogenic Therapy in Cancer

“…In in vitro experimental models, expression of CLPs depends on the activation state of macrophages (M1 or M2). YKL-40 expression is elevated during the differentiation process of human macrophages, and macrophage differentiation factors GM-CSF or M-CSF have been shown to induce YKL-40 expression (65,70). It was identified that in human monocyte-derived macrophages, IFNγ and LPS are strong inducers of YKL-40 gene expression (15,67).…”