RelB/p50 Complexes Regulate Cytokine-Induced YKL-40 Expression

Abstract

The secreted protein, YKL-40, has been proposed as a biomarker of a variety of human diseases characterized by ongoing inflammation, including chronic neurological pathologies such as multiple sclerosis (MS)2 and Alzheimer’s disease. However, inflammatory mediators and the molecular mechanism responsible for enhanced expression of YKL-40 remained elusive. Using several mouse models of inflammation, we now show that YKL-40 expression correlated with increased expression of both IL-1 and IL-6. Furthermore, IL-1 together with IL-6 or the IL-6 family cytokine, oncostatin M (OSM), synergistically upregulated YKL-40 expression in both primary human and mouse astrocytes in vitro. The robust cytokine-driven expression of YKL-40 in astrocytes required both STAT3 and NF-κB binding elements of the YKL-40 promoter. Additionally, YKL-40 expression was enhanced by constitutively active STAT3 and inhibited by dominant-negative IκBα. Surprisingly, cytokine-driven expression of YKL-40 in astrocytes was independent of the p65 subunit of NF-κB and instead required subunits RelB and p50. Mechanistically, we show that IL-1-induced RelB/p50 complex formation was further promoted by OSM and that these complexes directly bound to the YKL-40 promoter. Moreover, we found that expression of RelB was strongly upregulated during inflammation in vivo and by IL-1 in astrocytes in vitro. We propose that IL-1 and the IL-6 family of cytokines regulate YKL-40 expression during sterile inflammation via both STAT3 and RelB/p50 complexes. These results suggest that IL-1 may regulate the expression of specific anti-inflammatory genes in non-lymphoid tissues via the canonical activation of the RelB/p50 complexes.

Cerebrospinal Fluid Biomarkers of Simian Immunodeficiency Virus Encephalitis

“…We observed that YKL40 CSF levels correlate significantly with CSF cytokines such as IL1β, IL6 and osteopontin during the development of SIV encephalitis. Increases in these inflammatory mediators and others such as TNFα and C-reactive protein have been shown to correlate with CSF and CNS tissue YKL40 expression in other CNS inflammation models (Bonneh-Barkay et al, 2010b; Bhardwaj et al, 2015). The proinflammatory cytokines IL1β, IL6, oncostatin M, TNFα, and factors released from differentiating monocyte-derived macrophages have been shown to induce YKL40 expression in astrocytes (Singh et al, 2011; Bonneh-Barkay et al, 2012; Bhardwaj et al, 2015).…”

“…Increases in these inflammatory mediators and others such as TNFα and C-reactive protein have been shown to correlate with CSF and CNS tissue YKL40 expression in other CNS inflammation models (Bonneh-Barkay et al, 2010b; Bhardwaj et al, 2015). The proinflammatory cytokines IL1β, IL6, oncostatin M, TNFα, and factors released from differentiating monocyte-derived macrophages have been shown to induce YKL40 expression in astrocytes (Singh et al, 2011; Bonneh-Barkay et al, 2012; Bhardwaj et al, 2015). In the CNS, YKL40 induction is mostly restricted to astrocytes (Bonneh-Barkay et al, 2010a; Craig-Schapiro et al, 2010; Bonneh-Barkay et al, 2012) and is regulated by STAT3 and RelB/p50 complexes of NF-κB (Bhardwaj et al, 2015).…”

Transcriptome sequencing of neurologic diseases associated genes in HHV-6A infected human astrocyte

“…[94]. Significant expression differences of SERPINA1 (AAT) were identified as potential disease signatures for MS patients [95] and elevates in the cerebrospinal fluid of patients with MS [96]. CXCL16 could be a novel biomarker and potential predictor of disease activity in MS [97].…”

Chitinase 3-like 1 expression by human (MG63) osteoblasts in response to lysophosphatidic acid and 1,25-dihydroxyvitamin D3

“…Throughout this time, and despite the wealth of studies being reported, how YKL-40 expression might be regulated by local and systemic factors has received scant attention. Indeed this was raised recently by Bhardwaj and co-workers [37] wherein the authors state: "Despite the numerous reports documenting elevated expression of YKL-40, relatively little is known about the inflammatory mediators and specific molecular mechanisms that control its expression. "…”

“…There is good evidence supporting an important role of STAT3 in YKL-40 expression in the context of IL-1, IL-6 and oncostatin M-stimulated human and murine astrocytes [37,54]. We therefore set out to investigate …”