IL-25-induced activation of nasal fibroblast and its association with the remodeling of chronic rhinosinusitis with nasal polyposis.

Soo-Kyoung Park,Yong-De Jin,Yong-Min Kim,Rui-Ning Han,Jun Xu,Sun-Hee Yeon,Ki-Sang Rha,Yeong-Kyu Park,Zheng Liu

doi:10.1371/journal.pone.0181806

Abstract

Background and objectiveInterleukin (IL)-25 has been shown to play an important role in the pathogenesis of chronic rhinosinusitis with nasal polyps. Nasal polyps are associated with chronic inflammation of the mucous membranes in the paranasal sinuses and are involved in extracellular matrix (ECM) accumulation. The aim of this study is to evaluate the effects of IL-25 on myofibroblast differentiation, ECM production and the expression of matrix metalloproteinases in nasal polyp derived fibroblasts (NPDFs) and to determine the molecular mechanism underlying these processes.Materials and methodsA total of 40 patients were enrolled in this study for Immunofluorescence studies. Expression of IL17 receptor B was evaluated by real time reverse transcription polymerase chain reaction (PCR) in NPDFs. NPDFs were stimulated with IL-25 for 48 h in the presence or absence of mitogen-activated protein kinase (MAPK) and NF-κB inhibitors or small interfering RNAs (siRNA). The protein levels of fibrosis active mediators were examined using western blotting. Fibroblast migration was evaluated with a scratch assay. The total collagen amount was analyzed with the Sircol collagen assay.ResultsIL-25 induced α-SMA, fibronectin, and MMP-1 and -13, which were dependent on IL-17RB. IL-25 also induced activation of NF-κB and mitogen-activated protein kinase (MAPKs). By using the specific inhibitor of ERK, p38, JNK and NF-κB (U, SB, SP and Bay), we found that IL-25-induced expressions of α-SMA, fibronectin, and MMPs was regulated by the signaling pathways of MAPKs and NF-κB. IL-25 also induces α-SMA, fibronectin, and MMPs expression through IL-17RB-dependent pathways in NPDFs. The increased migration ability induced by IL-25 was suppressed by the specific inhibitors of MAPKs and NF-κB.ConclusionOur data indicate that IL-25 induced myofibroblast differentiation, fibronectin production, and MMP-1 and -13 expressions through the signaling pathways of MAPKs and NF-κB. in NPDFs and increased expression of IL-25 were also involved in the pathogenesis of nasal polyposis by affecting nasal fibroblasts in chronic rhinosinusitis with nasal polyps.

Highlights

Chronic rhinosinusitis with nasal polyposis (CRSwNP) is a chronic inflammatory disease of the paranasal sinuses whose underlying etiology is multifactorial in nature [1]
By using the specific inhibitor of ERK, p38, JNK and NF-κB (U, SB, SP and Bay), we found that IL-25-induced expressions of α-SMA, fibronectin, and MMPs was regulated by the signaling pathways of mitogen-activated protein kinase (MAPK) and NF-κB
Double immunofluorescent staining (Vimentin/ α-SMA or IL-25/ α-SMA) was conducted to investigate whether myofibroblasts were involved in pathogenesis of IL-25-induced activation of nasal fibroblast nasal polyp of the CRSwNP group. α-SMA and vimentin expression was observed in cytosol and IL-25 expression was observed in membrane

Summary

Introduction

Chronic rhinosinusitis with nasal polyposis (CRSwNP) is a chronic inflammatory disease of the paranasal sinuses whose underlying etiology is multifactorial in nature [1]. We previously reported that epithelial cells and fibroblasts, are two of the major components of the nasal polyp derived cells [3] and fibroblasts confer mechanical strength by providing a supporting framework for the extracellular matrix (ECM). Myofibroblasts that express alpha-smooth muscle actin (α-SMA) comprise an activated cell phenotype of fibroblasts with a high capacity for ECM protein secretion and play an important role in ECM remodeling of many pathologic conditions of the human airway, including asthma, chronic rhinosinusitis, and nasal polyps [7, 8]. Interleukin (IL)-25 has been shown to play an important role in the pathogenesis of chronic rhinosinusitis with nasal polyps. Nasal polyps are associated with chronic inflammation of the mucous membranes in the paranasal sinuses and are involved in extracellular matrix (ECM) accumulation. The aim of this study is to evaluate the effects of IL-25 on myofibroblast differentiation, ECM production and the expression of matrix metalloproteinases in nasal polyp derived fibroblasts (NPDFs) and to determine the molecular mechanism underlying these processes

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Conclusion