title: Tumor necrosis factor-α regulates interleukin-33 expression through extracellular signal-regulated kinase, p38, and nuclear factor-κB pathways in airway epithelial cells.
abstract: Interleukin (IL)-33 plays an important role in controlling immune responses in barrier tissues, and is a potent mediator of inflammatory diseases such as asthma, rheumatoid disease, and chronic rhinosinusitis. The aims of the present study were 2-fold: (1) to determine the stimulatory effect of tumor necrosis factor-α (TNF-α) on IL-33 production in nasal epithelial and A549 cells; and (2) to identify downstream pathways that activate IL-33 production.
  
  
  
  Primary nasal epithelial cells (PNECs) from 5 normal patients were isolated and cultured. To identify which cytokines stimulate IL-33 production, we performed reverse-transcription polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), and immunofluorescence staining. Three mitogen-activated protein kinases (MAPKs) (p38, extracellular signal-regulated kinase [ERK], and c-Jun N-terminal kinase [JNK]) and nuclear factor κB (NF-κB) were evaluated as downstream signaling molecules by RT-PCR, ELISA, Western blot analysis, and luciferase reporter assay.
  
  
  
  The IL-33 messenger RNA (mRNA) and protein levels were increased significantly by TNF-α in PNECs and A549 cells. TNF-α stimulated the expression of IL-33 in a dose- and time-dependent manner in A549 cells. PNECs and A549 cells were treated with TNF-α in the presence of specific inhibitors of p38, ERK, JNK, and NF-κB. In both cell types, inhibitors of ERK, p38, and NF-κB reversed TNF-α-induced IL-33 production. In the luciferase reporter assay, NF-κB activity was inhibited not only by an NF-κB inhibitor, but also by ERK and p38 inhibitors.
  
  
  
  TNF-α stimulated IL-33 expression through ERK, p38, and NFκB pathways in PNECs and A549 cells.
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, Korea University College of Medicine, Seoul, South Korea.
authors.forename: Il-Ho
authors.initials: IH
authors.lastname: Park
authors.affiliation: Department of Biomedical Sciences, Korea University Graduate School, Seoul, South Korea.
authors.forename: Joo-Hoo
authors.initials: JH
authors.lastname: Park
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, Korea University College of Medicine, Seoul, South Korea.
authors.forename: Jae-Min
authors.initials: JM
authors.lastname: Shin
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, Korea University College of Medicine, Seoul, South Korea. lhman@korea.ac.kr.|Department of Biomedical Sciences, Korea University Graduate School, Seoul, South Korea. lhman@korea.ac.kr.|IVD support Center, Guro Hospital, Korea University, Seoul, South Korea. lhman@korea.ac.kr.
authors.forename: Heung-Man
authors.initials: HM
authors.lastname: Lee
mesh_terms: D000072283:A549 Cells; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D000067596:Interleukin-33 / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D009297:Nasal Mucosa / Q000166:cytology; D012333:RNA, Messenger / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: C506536:IL33 protein, human; D000067596:Interleukin-33; D016328:NF-kappa B; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases
keywords: chronic rhinosinusitis; epithelium; interleukin-33; nose; tumor necrosis factor-alpha