Toll-like receptor 2-dependent NF-κB activation is involved in nontypeable haemophilus influenzae-induced monocyte chemotactic protein 1 up-regulation in the spiral ligament fibrocytes of the inner ear

Sung K. Moon, Jeong Im Woo, Haa Yung Lee, Raekil Park, Jun Shimada, Huiqi Pan, Robert Gellibolian, David J. Lim

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

Inner ear dysfunction secondary to chronic otitis media (OM), including high-frequency sensorineural hearing loss or vertigo, is not uncommon. Although chronic middle ear inflammation is believed to cause inner ear dysfunction by entry of OM pathogen components or cytokines from the middle ear into the inner ear, the underlying mechanisms are not well understood. Previously, we demonstrated that the spiral ligament fibrocyte (SLF) cell line up-regulates monocyte chemotactic protein 1 (MCP-1) expression after treatment with nontypeable Haemophilus influenzae (NTHI), one of the most common OM pathogens. We hypothesized that the SLF-derived MCP-1 plays a role in inner ear inflammation secondary to OM that is responsible for hearing loss and dizziness. The purpose of this study was to investigate the signaling pathway involved in NTHI-induced MCP-1 up-regulation in SLFs. Here we show for the first time that NTHI induces MCP-1 up-regulation in the SLFs via Toll-like receptor 2 (TLR2)-dependent activation of NF-κB. TLR2-/-- and MyD88 _/--derived SLFs revealed involvement of TLR2 and MyD88 in NTHI-induced MCP-1 up-regulation. Studies using chemical inhibitors and dominant-negative constructs demonstrated that it is mediated by the IκKβ-dependent IκBα phosphorylation and NTHI-induced NF-κB nuclear translocation. Furthermore, we demonstrated that the binding of NF-κB to the enhancer region of MCP-1 is involved in this up-regulation. In addition, we have identified a potential NF-κB motif that is responsive and specific to certain NTHI molecules or ligands. Further studies are necessary to reveal specific ligands of NTHI that activate host receptors. These results may provide us with new therapeutic strategies for prevention of inner ear dysfunction secondary to chronic middle ear inflammation.

Original languageEnglish (US)
Pages (from-to)3361-3372
Number of pages12
JournalInfection and Immunity
Volume75
Issue number7
DOIs
StatePublished - Jul 2007

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Infectious Diseases

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