title: Cold-inducible RNA-binding protein mediates cold air inducible airway mucin production through TLR4/NF-κB signaling pathway.
abstract: Mucus overproduction is an important feature in patients with chronic inflammatory airway diseases and cold air stimulation has been shown to be associated with the severity of these diseases. However, the regulatory mechanisms that mediate excessive mucin production under cold stress remain elusive. Recently, the cold-inducible RNA-binding protein (CIRP) has been shown to be markedly induced after exposure to cold air. In this study, we sought to explore the expression of CIRP within bronchial biopsy specimens, the effect on mucin5AC (MUC5AC) production in chronic inflammatory airway diseases and the potential signaling pathways involved in cold air stimulation process. We found that CIRP protein expression was significantly increased in patients with COPD and in mice treated with cold air. Moreover, cold air stimulation induced MUC5AC expression in wild-type mice but not in CIRP(-/-) mice. In vitro, cold air stress significantly elevated the transcriptional and protein expression levels of MUC5AC in human bronchial epithelial cells. CIRP, toll-like receptor 4 (TLR4) and phosphorylated NF-κB p65 (p-p65) increased significantly in response to cold stress and CIRP siRNA, TLR4 - neutralizing Ab and a specific inhibitor of NF-κB could attenuated cold stress inducible MUC5AC expression. In addition, CIRP siRNA could hindered the expression levels of TLR4 and p-p65 both induced by cold stress. Taken together, these results suggest that airway epithelial cells constitutively express CIRP in vitro and in vivo. CIRP is responsible for cold-inducible MUC5AC expression by activating TLR4/NF-κB signaling pathway.
authors.affiliation: Department of Respiratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, No. 74, Linjiang Road, Yuzhong District, Chongqing 400010, China. Electronic address: 549482835@qq.com.
authors.forename: Lingxiu
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Respiratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, No. 74, Linjiang Road, Yuzhong District, Chongqing 400010, China. Electronic address: 513913449@qq.com.
authors.forename: Danhua
authors.initials: D
authors.lastname: Ran
authors.affiliation: Department of Respiratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, No. 74, Linjiang Road, Yuzhong District, Chongqing 400010, China. Electronic address: 115962845@qq.com.
authors.forename: Wenyue
authors.initials: W
authors.lastname: Xie
authors.affiliation: Department of Respiratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, No. 74, Linjiang Road, Yuzhong District, Chongqing 400010, China. Electronic address: 531586182@qq.com.
authors.forename: Qing
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Department of Respiratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, No. 74, Linjiang Road, Yuzhong District, Chongqing 400010, China. Electronic address: zxd999@263.net.
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Zhou
mesh_terms: D000328:Adult; D000368:Aged; D056809:Alveolar Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D003080:Cold Temperature; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D055271:Mucin 5AC / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: C491390:CIRBP protein, human; D055271:Mucin 5AC; D016328:NF-kappa B; D016601:RNA-Binding Proteins; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4
keywords: Cold air; Cold-inducible RNA-binding protein; Mucin5AC; Nuclear transcription factor-κB; Toll-like receptor 4