Park Soo-Kyoung, Jin Yong-De, Park Yeong-Kyu, Yeon Sun-Hee, Xu Jun, Han Rui-Ning, Rha Ki-Sang, Kim Yong-Min
Department of Otorhinolaryngology-Head and Neck Surgery, Research Institute for Medical Science, Chungnam National University School of Medicine, Daejeon, Korea.
Department of Otorhinolaryngology-Head and Neck Surgery, Yanbian University Hospital, Yanji, China.
PLoS One. 2017 Aug 3;12(8):e0181806. doi: 10.1371/journal.pone.0181806. eCollection 2017.
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.
A 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.
IL-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.
Our 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.
白细胞介素（IL）-25已被证明在伴鼻息肉的慢性鼻-鼻窦炎发病机制中起重要作用。鼻息肉与鼻窦黏膜的慢性炎症相关，并参与细胞外基质（ECM）的积聚。本研究的目的是评估IL-25对鼻息肉来源的成纤维细胞（NPDFs）中肌成纤维细胞分化、ECM产生及基质金属蛋白酶表达的影响，并确定这些过程的分子机制。
本研究共纳入40例患者进行免疫荧光研究。通过实时逆转录聚合酶链反应（PCR）评估NPDFs中IL17受体B的表达。在有或无丝裂原活化蛋白激酶（MAPK）和核因子κB（NF-κB）抑制剂或小干扰RNA（siRNA）的情况下，用IL-25刺激NPDFs 48小时。使用蛋白质印迹法检测纤维化活性介质的蛋白水平。用划痕试验评估成纤维细胞迁移。用Sircol胶原测定法分析总胶原量。
IL-25诱导α-平滑肌肌动蛋白（α-SMA）、纤连蛋白以及基质金属蛋白酶（MMP）-1和-13，这依赖于IL-17RB。IL-25还诱导NF-κB和丝裂原活化蛋白激酶（MAPKs）的激活。通过使用细胞外信号调节激酶（ERK）、p38、应激活化蛋白激酶（JNK）和NF-κB的特异性抑制剂（U、SB、SP和Bay），我们发现IL-25诱导的α-SMA、纤连蛋白和MMPs的表达受MAPKs和NF-κB信号通路调控。IL-25还通过NPDFs中依赖IL-17RB的途径诱导α-SMA、纤连蛋白和MMPs表达。IL-25诱导的迁移能力增加被MAPKs和NF-κB的特异性抑制剂抑制。
我们的数据表明，IL-25通过MAPKs和NF-κB信号通路诱导NPDFs中的肌成纤维细胞分化、纤连蛋白产生以及MMP-1和-13表达。IL-25表达增加也通过影响伴鼻息肉的慢性鼻-鼻窦炎中的鼻成纤维细胞参与鼻息肉病的发病机制。
