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

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-kappaB. 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 IkappaKbeta-dependent IkappaBalpha phosphorylation and NTHI-induced NF-kappaB nuclear translocation. Furthermore, we demonstrated that the binding of NF-kappaB to the enhancer region of MCP-1 is involved in this up-regulation. In addition, we have identified a potential NF-kappaB 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.

journal_name

Infect Immun

journal_title

Infection and immunity

authors

Moon SK,Woo JI,Lee HY,Park R,Shimada J,Pan H,Gellibolian R,Lim DJ

doi

10.1128/IAI.01886-06

subject

Has Abstract

pub_date

2007-07-01 00:00:00

pages

3361-72

issue

eissn

0019-9567

issn

1098-5522

pii

IAI.01886-06

journal_volume

pub_type

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