title: Toll-like receptor 4-mediated expression of interleukin-32 via the c-Jun N-terminal kinase/protein kinase B/cyclic adenosine monophosphate response element binding protein pathway in chronic rhinosinusitis with nasal polyps.
abstract: Chronic rhinosinusitis with nasal polyps (CRSwNP) is prolonged inflammation of the sinonasal mucosa. Interleukin-32 (IL-32) is involved in the pathogenesis of chronic lung inflammatory diseases. The aim of study is to compare the expression level of IL-32 in normal nasal mucosa and CRSwNP and to investigate the mechanism underlying IL-32 expression in CRSwNP.
  
  
  
  IL-32 expression in nasal tissues, normal nasal mucosa-derived fibroblasts (NorDFs) and nasal polyp-derived fibroblasts (NPDFs), ex vivo explants of nasal tissues was measured by reverse-transcription polymerase chain reaction (RT-PCR), Western blotting, and enzyme-linked immunosorbent assay (ELISA). NorDFs and NPDFs were exposed to lipopolysaccharide (LPS) and the expression level of IL-32 was measured. LPS from Rhodobactersphaeroides (RS) and small interference RNA against Toll-like receptor 4 (siTLR4) were used to inhibit signaling by TLR4. Activation of mitogen-activated protein kinase (MAPKs) (extracellular related kinase [ERK], p38, and c-Jun N-terminal kinase [JNK]), protein kinase B (AKT), and cyclic adenosine monophosphate response element binding protein (CREB) was examined using western blot analysis.
  
  
  
  Expression of IL-32 was increased in CRSwNP compared to normal nasal mucosa. LPS induced expression of IL-32 in a time-dependent manner. The induction of IL-32 expression in NPDFS was more effective than in NorDFs. Treatment with RS and siTLR4 inhibited the messenger RNA (mRNA) expression of TLR4, myeloid differentiation primary response 88 (MyD88), and IL-32 in LPS-stimulated NPDFs. IL-32 expression was specifically activated by JNK, AKT, and CREB in LPS-stimulated NPDFs and CRSwNP ex vivo explants.
  
  
  
  The sensitivity for IL-32 expression by LPS was increased in CRSwNP compared to normal nasal mucosa. LPS effectively induced IL-32 expression in NPDFs than in NorDFs through the TLR4-JNK-AKT-CREB signaling pathway. Therefore, IL-32 seems to be involved in the pathogenesis of CRSwNP.
authors.affiliation: Biomedical Science, Korea University Guro Hospital, Korea University, College of Medicine, Seoul, Korea.|Institute for Medical Devices Clinical Trial Center, Korea University Guro Hospital, Korea University, College of Medicine, Seoul, South Korea.
authors.forename: Jung-Sun
authors.initials: JS
authors.lastname: Cho
authors.affiliation: Biomedical Science, Korea University Guro Hospital, Korea University, College of Medicine, Seoul, Korea.
authors.forename: Jin-Ah
authors.initials: JA
authors.lastname: Kim
authors.affiliation: Biomedical Science, Korea University Guro Hospital, Korea University, College of Medicine, Seoul, Korea.
authors.forename: Joo-Hoo
authors.initials: JH
authors.lastname: Park
authors.affiliation: Institute for Medical Devices Clinical Trial Center, Korea University Guro Hospital, Korea University, College of Medicine, Seoul, South Korea.|Department of Otorhinolaryngology- Head and Neck Surgery, Korea University Guro Hospital, Korea University, College of Medicine, Seoul, South Korea.
authors.forename: Il-Ho
authors.initials: IH
authors.lastname: Park
authors.affiliation: Biomedical Science, Korea University Guro Hospital, Korea University, College of Medicine, Seoul, Korea.
authors.forename: In-Hye
authors.initials: IH
authors.lastname: Han
authors.affiliation: Biomedical Science, Korea University Guro Hospital, Korea University, College of Medicine, Seoul, Korea. lhman@korea.ac.kr.|Institute for Medical Devices Clinical Trial Center, Korea University Guro Hospital, Korea University, College of Medicine, Seoul, South Korea. lhman@korea.ac.kr.|Department of Otorhinolaryngology- Head and Neck Surgery, Korea University Guro Hospital, Korea University, College of Medicine, Seoul, South Korea. lhman@korea.ac.kr.|Research-Driven Hospital, Korea University Guro Hospital, Korea University, College of Medicine, Seoul, South Korea. lhman@korea.ac.kr.
authors.forename: Heung-Man
authors.initials: HM
authors.lastname: Lee
mesh_terms: D002478:Cells, Cultured; D002908:Chronic Disease; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D009297:Nasal Mucosa / Q000166:cytology / Q000378:metabolism; D009298:Nasal Polyps / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012220:Rhinitis / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D012852:Sinusitis / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; C496971:IL32 protein, human; D007378:Interleukins; D008070:Lipopolysaccharides; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases
keywords: Toll-like receptor; chronic rhinosinusitis; ex vivo explant; fibroblast; interleukin-32; nasal polyp