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Infect. Immun. doi:10.1128/IAI.01886-06
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Toll-like receptor 2-dependent NFB activation is involved in nontypeable Haemophilus influenzae-induced MCP-1 up-regulation in the spiral ligament fibrocytes of the inner ear

The Gonda Department of Cell and Molecular Biology, House Ear Institute, Los Angeles, CA, USA; Department of Otolaryngology, Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

^* To whom correspondence should be addressed. Email: dlim{at}hei.org.

	Abstract

Inner ear dysfunction secondary to chronic otitis media (OM) is not uncommon, including high-frequency sensorineural hearing loss or vertigo. 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 are hypothesizing that the SLF-derived MCP-1 plays a role in inner ear inflammation secondary to OM, responsible for hearing loss and dizziness. The purpose of this study is 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 TLR2-dependent activation of NFB. 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 IK-dependent IB phosphorylation and NTHi-induced NFB nuclear translocation. Furthermore, we demonstrated that the binding of NFB to the enhancer region of MCP-1 is involved in this up-regulation. In addition, we have identified a potential NFB motif, responsive and specific to certain NTHi molecules or ligands. Further studies are necessary to reveal specific ligands of NTHi, activating host receptors. These results may provide us with new therapeutic strategies for prevention of inner ear dysfunction secondary to chronic middle ear inflammation.