IL-19 Induced by IL-13/IL-17A in the Nasal Epithelium of Patients with Chronic Rhinosinusitis Upregulates MMP-9 Expression via ERK/NF-kB Signaling Pathway

Abstract

Background: Tissue remodeling is a crucial characteristic of chronic rhinosinusitis (CRS). Imbalance between matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) is crucial for the pathologic tissue remodeling in CRS. Elevation of interleukin (IL)-19 or MMP-9 levels in patients with CRS had been proven in previous studies. Here, we aimed to investigate the role of IL-19 in mediating MMP-9 expression in CRS. Methods: Nasal tissue samples were collected from 45 individuals having chronic rhinosinusitis with nasal polyps (CRSwNP), 24CRS without nasal polyps (CRSsNP), and 17 controls. Expression of IL-19, its receptors (IL-20R1/IL-20R2), and MMP-9 were investigated using RT-qPCR and Immunofluorescence. Human nasal epithelial cells (HNECs) were stimulated by IL-19; ERK phosphorylation, NF-kB pathway activation, and MMP-9 level were detected by RT-qPCR, ELISA, western blot and Immunofluorescence. We also explored the effect of type1/2/3 cytokines on IL-19 production by RT-qPCR, and western blot. Results: Expression levels of IL-19, its receptors (IL-20R1/IL-20R2), and MMP-9 were increased in nasal tissues from individuals with CRSwNP compared to those with CRSsNP as well as the controls. IL-19 significantly elevated the production of MMP-9 in HNECs. Furthermore, IL-19 could activate the ERK and NF-kB pathways, accompanied by increased MMP-9 production in HNECs. Conversely, both ERK and NF-kB inhibitors significantly attenuated the role of IL-19 in MMP-9 production. siRNA knockdown of IL-20R1 suppressed ERK and NF-kB pathway activation, thereby decreasing MMP-9 expression. IL-13 and IL-17A were found to stimulate IL-19 production in HNECs.Conclusion: IL-19, promoted by IL-13 and IL-17A, contributes to the upregulation of secretion of the tissue remodeling factor MMP-9 in patients with CRS.