title: Toll-like receptor ligands induce cytokine and chemokine production in human inner ear endolymphatic sac fibroblasts.
abstract: OBJECTIVE
  Against recent reports concerning cytokine or chemokine in mouse or rat inner ear cells, it is almost unknown whether human inner ear cells would produce cytokine or chemokine. We have for the first time established the human inner-ear-derived fibroblasts from endolymphatic sac.
  
  
  METHODS
  The expression levels of Toll-like receptors (TLRs) in human endolymphatic sac fibroblasts, and the effect on cytokine or chemokine production of the TLR ligands have been examined. To demonstrate the intracellular pathways involved in the regulation of cytokine-production, we used specific inhibitors of c-Jun N-terminal kinase (JNK), extracellular signal-related kinase (ERK), p38 mitogen-activated protein kinase (p38 MAPK)-signaling and N-acetyl-l-cysteine (NAC).
  
  
  RESULTS
  TLR 2, 3, 4 and 9 were highly expressed in human endolymphatic sac fibroblasts. The TLR 3 ligand, polyinosinic-polycytidylic acid (poly(I:C)) significantly enhanced the secretion of thymic stromal lymphopoietin (TSLP), B lymphocyte stimulator (BLyS), IFNγ-inducible protein 10 (IP-10), and macrophage inflammatory protein 1 alpha (MIP-1α) from the cells. The inhibitor of JNK strongly reduced the poly(I:C)-induced TSLP-production. The antioxidant drug, NAC also reduced the TSLP-production in fibroblasts stimulated with poly(I:C).
  
  
  CONCLUSIONS
  Our findings suggest human inner-ear-endolymphatic sac derived fibroblasts can produce the cytokine and chemokine in response to TLR ligands and play a certain role during the initiation of an immune response.
authors.affiliation: Department of Otorhinolaryngology, University of Fukui, Fukui 910-1193, Japan; Department of Otorhinolaryngology, Akita University Graduate School of Medicine, Akita 010-8543, Japan. Electronic address: ymdtkcy@gmail.com.
authors.forename: Takechiyo
authors.initials: T
authors.lastname: Yamada
authors.affiliation: Department of Otorhinolaryngology, University of Fukui, Fukui 910-1193, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ogi
authors.affiliation: Department of Otorhinolaryngology, University of Fukui, Fukui 910-1193, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Sakashita
authors.affiliation: Department of Otorhinolaryngology, University of Fukui, Fukui 910-1193, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kanno
authors.affiliation: Department of Otorhinolaryngology, University of Fukui, Fukui 910-1193, Japan.
authors.forename: Seita
authors.initials: S
authors.lastname: Kubo
authors.affiliation: Department of Otorhinolaryngology, University of Fukui, Fukui 910-1193, Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Ito
authors.affiliation: Department of Otorhinolaryngology, University of Fukui, Fukui 910-1193, Japan.
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Imoto
authors.affiliation: Department of Otorhinolaryngology, University of Fukui, Fukui 910-1193, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Tokunaga
authors.affiliation: Department of Otorhinolaryngology, University of Fukui, Fukui 910-1193, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Okamoto
authors.affiliation: Department of Otorhinolaryngology, University of Fukui, Fukui 910-1193, Japan.
authors.forename: Norihiko
authors.initials: N
authors.lastname: Narita
authors.affiliation: Department of Otorhinolaryngology, University of Fukui, Fukui 910-1193, Japan.
authors.forename: Shigeharu
authors.initials: S
authors.lastname: Fujieda
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D048868:Adaptor Proteins, Signal Transducing / Q000187:drug effects / Q000378:metabolism; D053264:B-Cell Activating Factor / Q000187:drug effects / Q000378:metabolism; D054357:Chemokine CXCL10 / Q000187:drug effects / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism*; D004712:Endolymphatic Sac / Q000166:cytology / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D005347:Fibroblasts / Q000378:metabolism*; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D011070:Poly I-C / Q000494:pharmacology; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051196:Toll-Like Receptor 3 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D000094632:Thymic Stromal Lymphopoietin
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D053264:B-Cell Activating Factor; C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D018925:Chemokines; D016207:Cytokines; D016166:Free Radical Scavengers; C493277:MAPKAP1 protein, human; C495342:TLR2 protein, human; C495344:TLR3 protein, human; C495345:TLR4 protein, human; C495371:TLR9 protein, human; C505719:TNFSF13B protein, human; D051195:Toll-Like Receptor 2; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D011070:Poly I-C; D000111:Acetylcysteine; D000094632:Thymic Stromal Lymphopoietin
keywords: Cytokine; Endolymphatic sac; Fibroblasts; Inner ear; Toll-like receptor ligands