Interleukin-19 upregulates fibronectin and collagen I expression via the NF-κB-Smad2/3 pathway in fibroblasts of patients with chronic rhinosinusitis

Abstract BackgroundChronic sinusitis without nasal polyps (CRSsNP), a subtype of chronic rhinosinusitis, is characterized by tissue remodeling, mainly by interstitial fibrosis. Fibroblasts are essential effectors of tissue remodeling, mainly expressing fibronectin (FN), collagen Ι (Col Ι), and other extracellular matrices. Our previous study found that IL-19 can promote the aberrant expression of extracellular matrix, and pre-experiments revealed that the Smad2/3 pathway plays a crucial role in tissue remodeling. However, the exact mechanism how IL-19 participants in tissue remodeling remains unclear. This study aimed to determine the roles of IL-19 in regulating the expression of FN and Col Ι, and the roles of Smad2/3 and NF-κB signaling pathways in fibroblasts.MethodsNasal mucosal tissue samples were collected from patients with chronic sinusitis with nasal polyps (CRSwNP), patients with CRSsNP, and controls to analyze the expression of IL-19, FN, and Col Ι by RT-qPCR, immunohistochemistry, immunofluorescence, or western blotting. Cultured primary human nasal mucosal fibroblasts were treated with human recombinant IL-19 with or without Smad2/3 and NF-κB pathway inhibitor or agonist. They were analyzed for Smad2/3 and NF-κB pathway activation, and FN and Col Ι expression in fibroblasts by western blot, immunohistochemistry, and immunofluorescence.ResultsIL-19 co-localized with FN and Col Ι in nasal mucosal tissues and the expression levels of FN and Col Ι were elevated in CRSsNP, compared with CRSwNP and the control group. IL-19 activated the Smad2/3 and NF-κB pathways and promoted FN and Col Ι production in fibroblasts. NF-κB functions as an upstream pathway of the Smad2/3 pathway. The inhibitors of Smad2/3 and NF-κB could significantly attenuate the expression of FN and Col Ι induced by IL-19. ConclusionIL-19 promotes FN and Col Ι expression in fibroblasts via the NF-κB-Smad2/3 signaling pathway, leading to fibrosis and collagen deposition in patients with CRSsNP.