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Infection and Immunity, July 2007, p. 3361-3372, Vol. 75, No. 7
0019-9567/07/$08.00+0 doi:10.1128/IAI.01886-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.
Toll-Like Receptor 2-Dependent NF-
B 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,1
Jeong-Im Woo,1
Haa-Yung Lee,1
Raekil Park,1,
Jun Shimada,1,
Huiqi Pan,1
Robert Gellibolian,1 and
David J. Lim1,2,3*
The Gonda Department of Cell and Molecular Biology, House Ear Institute, Los Angeles, California,1 Department of Otolaryngology,2 Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles, California3
Received 29 November 2006/ Returned for modification 18 January 2007/ Accepted 11 April 2007
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-
B. 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 IKß-dependent IB
phosphorylation and NTHI-induced NF-B nuclear translocation. Furthermore, we demonstrated that the binding of NF-B to the enhancer region of MCP-1 is involved in this up-regulation. In addition, we have identified a potential NF-B 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.
* Corresponding author. Mailing address: The Gonda Department of Cell and Molecular Biology, House Ear Institute, 2100 West 3rd Street, Los Angeles, CA 90057. Phone: (213) 353-7021. Fax: (213) 483-5675. E-mail: dlim{at}hei.org
Published ahead of print on 23 April 2007.
Present address: Vestibulocochlear Research Center and Department of Microbiology, Wonkwang University School of Medicine, Iksan Chonbuk, South Korea.
Present address: Department of Otolaryngology, Wakayama Medical University, Wakayama, Japan.
Infection and Immunity, July 2007, p. 3361-3372, Vol. 75, No. 7
0019-9567/07/$08.00+0 doi:10.1128/IAI.01886-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.
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