Abstract
The hexosamine biosynthetic pathway (HBP) generates the substrate for the O-linked β-N-acetylglucosamine (O-GlcNAc) modification of proteins. The HBP also serves as a stress sensor and has been reported to be involved with nuclear factor of activated T-cells (NFAT) activation, which can contribute to multiple cellular processes including cell metabolism, proliferation, and inflammation. In our previously published report, Fibroblast Growth Factor (FGF) 23, an important endocrine pro-inflammatory mediator, was shown to activate the FGFR4/phospholipase Cγ (PLCγ)/nuclear factor of activated T-cells (NFAT) signaling in chronic inflammatory airway diseases such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). Here, we demonstrate that FGF23 increased the O-GlcNAc modification of proteins in HBECs. Furthermore, the increase in O-GlcNAc levels by FGF23 stimulation resulted in the downstream activation of NFAT and secretion of interleukin-6 (IL-6). Conversely, inhibition of FGF23 signaling and/or O-GlcNAc transferase (OGT)/O-GlcNAc reversed these effects. Collectively, these data suggest that FGF23 induced IL-6 upregulation and secretion is, at least, partially mediated via the activation of the HBP and O-GlcNAc levels in HBECs. These findings identify a novel link whereby FGF23 and the augmentation of O-GlcNAc levels regulate airway inflammation through NFAT activation and IL-6 upregulation in HBECs. The crosstalk between these signaling pathways may contribute to the pathogenesis of chronic inflammatory airway diseases such as COPD and CF as well as metabolic syndromes, including diabetes.
Highlights
Human fibroblast growth factors (FGFs) are classified as intracrine, paracrine, and endocrine Fibroblast Growth Factor (FGF) depending on their action process with endocrine FGFs playing key roles in metabolism including bile acid, energy, and phosphate/active vitamin D metabolism [1, 2]
To determine whether the changes in O-GlcNAc following FGF23 are regulated through the phospholipase Cγ (PLCγ) signaling pathway, we blocked PLCγ activation using a PLCγ inhibitor (U-73122), which has been shown to block FGF23 signaling through FGFR4 [27, 28]
O-GlcNAc transferase (OGT) and OGA protein levels were decreased after PLCγ blockade (Figures 1H,J,K: OGT NT: 1.30 ± 0.15; 0.1 μM PLCγ inhibitor: 1.00 ± 0.08; 1.0 μM PLCγ inhibitor: 0.64 ± 0.10; p = 0.0073 and OGA NT: 1.08 ± 0.08; 0.1 μM PLCγ inhibitor: 0.91 ± 0.10; 1.0 μM PLCγ inhibitor: 0.57 ± 0.05; p = 0.0045) Altogether, these data suggest that FGF23 activates the PLCγ signaling pathway that regulates the O-GlcNAc changes observed in human bronchial epithelial cells (HBECs)
Summary
Human fibroblast growth factors (FGFs) are classified as intracrine, paracrine, and endocrine FGFs depending on their action process with endocrine FGFs playing key roles in metabolism including bile acid, energy, and phosphate/active vitamin D metabolism [1, 2]. FGF23 is a 27-kDa protein that has been shown to be strongly associated with the risk of chronic kidney disease progression, systemic inflammation, and mortality [3, 4]. Our recent data characterized FGF23 signaling as an important mediator in inflammatory airway diseases such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) [5, 6]. In the COPD lung, FGF23 activated the FGF23 and O-GlcNAc regulates IL-6 phospholipase Cγ (PLCγ)/nuclear factor of activated T-cells (NFAT) signaling pathway leading to airway inflammation[5]. NFAT signaling has been linked to inflammatory cytokine production in hepatocytes, angiogenesis, cardiomyocyte hypertrophy, and many other biological processes [7,8,9,10]. NFAT interacts with multiple factors to regulate gene expression of molecules involved in the aforementioned disease processes
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