title: Toluene diisocyanate exposure induces airway inflammation of bronchial epithelial cells via the activation of transient receptor potential melastatin 8.
abstract: Toluene diisocyanate (TDI) is the most important cause of occupational asthma (OA), and various pathogenic mechanisms have been suggested. Of these mechanisms, neurogenic inflammation is an important inducer of airway inflammation. Transient receptor potential melastatin 8 (TRPM8) is a well-established cold-sensing cation channel that is expressed in both neuronal cells and bronchial epithelial cells. A recent genome-wide association study of TDI-exposed workers found a significant association between the phenotype of TDI-induced OA and the single-nucleotide polymorphism rs10803666, which has been mapped to the TRPM8 gene. We hypothesized that TRPM8 located in airway epithelial cells may be involved in the pathogenic mechanisms of TDI-induced OA and investigated its role. Bronchial epithelial cells were treated with TDI in a dose- and time-dependent manner. The expression levels of TRPM8 mRNA and protein were determined by quantitative real-time polymerase chain reaction and western blotting. TDI-induced morphological changes in the cells were evaluated by immunocytochemistry. Alterations in the transcripts of inflammatory cytokines were examined in accordance with TRPM8 activation by TDI. TRPM8 expression at both the mRNA and protein levels was enhanced by TDI in airway epithelial cells. TRPM8 activation by TDI led to significant increases in the mRNA of interleukin (IL)-4, IL-13, IL-25 and IL-33. The increased expression of the cytokine genes by TDI was partly attenuated after treatment with a TRPM8 antagonist. TDI exposure induces increased expression of TRPM8 mRNA in airway epithelial cells coupled with enhanced expression of inflammatory cytokines, suggesting a novel role of TRPM8 in the pathogenesis of TDI-induced OA.
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, South Korea.
authors.forename: Joo-Hee
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, South Korea.
authors.forename: Young-Sook
authors.initials: YS
authors.lastname: Jang
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, South Korea.
authors.forename: Seung-Hun
authors.initials: SH
authors.lastname: Jang
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, South Korea.
authors.forename: Ki-Suck
authors.initials: KS
authors.lastname: Jung
authors.affiliation: Department of Allergy and Clinical Immunology, Ajou Research Institute for Innovation Medicine, Ajou University Medical Center, Suwon, South Korea.
authors.forename: Seung-Hyun
authors.identifier: 0000-0003-1789-8964
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Allergy and Clinical Immunology, Ajou Research Institute for Innovation Medicine, Ajou University Medical Center, Suwon, South Korea.
authors.forename: Young-Min
authors.initials: YM
authors.lastname: Ye
authors.affiliation: Department of Allergy and Clinical Immunology, Ajou Research Institute for Innovation Medicine, Ajou University Medical Center, Suwon, South Korea.
authors.forename: Hae-Sim
authors.initials: HS
authors.lastname: Park
mesh_terms: D001980:Bronchi / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D006801:Humans; D007249:Inflammation / Q000209:etiology / Q000378:metabolism; D007378:Interleukins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism*; D050053:TRPM Cation Channels / Q000235:genetics* / Q000378:metabolism; D014051:Toluene 2,4-Diisocyanate / Q000633:toxicity
chemical_list: D007378:Interleukins; D012333:RNA, Messenger; D050053:TRPM Cation Channels; C425966:TRPM8 protein, human; D014051:Toluene 2,4-Diisocyanate