title: ERK2-dependent activation of c-Jun is required for nontypeable Haemophilus influenzae-induced CXCL2 upregulation in inner ear fibrocytes.
abstract: The inner ear, composed of the cochlea and the vestibule, is a specialized sensory organ for hearing and balance. Although the inner ear has been known as an immune-privileged organ, there is emerging evidence indicating an active immune reaction of the inner ear. Inner ear inflammation can be induced by the entry of proinflammatory molecules derived from middle ear infection. Because middle ear infection is highly prevalent in children, middle ear infection-induced inner ear inflammation can impact the normal development of language and motor coordination. Previously, we have demonstrated that the inner ear fibrocytes (spiral ligament fibrocytes) are able to recognize nontypeable Haemophilus influenzae, a major pathogen of middle ear infection, and upregulate a monocyte-attracting chemokine through TLR2-dependent NF-κB activation. In this study, we aimed to determine the molecular mechanism involved in nontypeable H. influenzae-induced cochlear infiltration of polymorphonuclear cells. The rat spiral ligament fibrocytes were found to release CXCL2 in response to nontypeable H. influenzae via activation of c-Jun, leading to the recruitment of polymorphonuclear cells to the cochlea. We also demonstrate that MEK1/ERK2 signaling pathway is required for nontypeable H. influenzae-induced CXCL2 upregulation in the rat spiral ligament fibrocytes. Two AP-1 motifs in the 5'-flanking region of CXCL2 appeared to function as a nontypeable H. influenzae-responsive element, and the proximal AP-1 motif was found to have a higher binding affinity to nontypeable H. influenzae-activated c-Jun than that of the distal one. Our results will enable us better to understand the molecular pathogenesis of middle ear infection-induced inner ear inflammation.
authors.affiliation: Division of Clinical and Translational Research, House Research Institute, Los Angeles, CA 90057, USA.
authors.forename: Sejo
authors.initials: S
authors.lastname: Oh
authors.forename: Jeong-Im
authors.initials: JI
authors.lastname: Woo
authors.forename: David J
authors.initials: DJ
authors.lastname: Lim
authors.forename: Sung K
authors.initials: SK
authors.lastname: Moon
mesh_terms: D000818:Animals; D001665:Binding Sites; D002460:Cell Line / Q000378:metabolism / Q000382:microbiology; D002465:Cell Movement; D002478:Cells, Cultured / Q000378:metabolism / Q000382:microbiology; D054426:Chemokine CXCL2 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation; D006193:Haemophilus influenzae / Q000276:immunology*; D048369:MAP Kinase Kinase 1 / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology*; D016297:Mutagenesis, Site-Directed; D010033:Otitis Media / Q000276:immunology; D016755:Proto-Oncogene Proteins c-jun / Q000502:physiology*; D051381:Rats; D011993:Recombinant Fusion Proteins; D015398:Signal Transduction; D013045:Species Specificity; D055493:Spiral Ligament of Cochlea / Q000166:cytology*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation
chemical_list: D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; C513296:Cxcl2 protein, rat; D016755:Proto-Oncogene Proteins c-jun; D011993:Recombinant Fusion Proteins; D018808:Transcription Factor AP-1; D019950:Mitogen-Activated Protein Kinase 1; D048369:MAP Kinase Kinase 1