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J. Biol. Chem., Vol. 280, Issue 43, 36185-36194, October 28, 2005

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Epidermal Growth Factor Receptor Acts as a Negative Regulator for Bacterium Nontypeable Haemophilus influenzae-induced Toll-like Receptor 2 Expression via an Src-dependent p38 Mitogen-activated Protein Kinase Signaling Pathway^*

Fumi Mikami, He Gu, Hirofumi Jono, Ali Andalibi, Hirofumi Kai, and Jian-Dong Li1

From the Gonda Department of Cell and Molecular Biology, House Ear Institute, and the Department of Otolaryngology, University of Southern California, Los Angeles, California 90057 and the Department of Molecular Medicine, Kumamoto University, Kumamoto 862-0973, Japan

Epidermal growth factor receptor (EGFR) has been shown to play important roles in regulating diverse biological processes, including cell growth, differentiation, apoptosis, adhesion, and migration. Its role in regulating human Toll-like receptors (TLRs), key host defense receptors that recognize invading bacterial pathogens, however, remains unknown. Here we show for the first time that EGFR acts as a negative regulator for TLR2 induction by the bacterium nontypeable Haemophilus influenzae (NTHi) in vitro and in vivo. The negative regulation of TLR2 induction by EGFR is mediated via an Src-MKK3/6-p38 / MAP kinase-dependent mechanism. Moreover, direct activation of EGFR signaling by the bacterium NTHi-derived EGF-like factor appears to be responsible for triggering the downstream Src-MKK3/6-p38 MAPK signaling, which in turn leads to the negative regulation of TLR2 induction. Finally, exogenous EGF increases NTHi invasion of host epithelial cells, thereby demonstrating the biological significance of TLR2 regulation by EGFR signaling. The evidence we provided in the present study may suggest a novel strategy utilized by bacteria to attenuate host defensive and immune response by negatively regulating the expression of host defense receptor TLR2. These studies may bring new insight for fully understanding the important role of EGFR signaling in regulating host defense and immune response by tightly controlling TLR2 induction during bacterial infections.

Received for publication, April 12, 2005 , and in revised form, August 17, 2005.

^* This work was supported by National Institutes of Health Grants HL070293, DC005843, and DC004562 (to J.-D. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Gonda Dept. of Cell and Molecular Biology, House Ear Institute, University of Southern California, 2100 West Third St., Los Angeles, CA 90057. Tel.: 213-273-8083; Fax: 213-273-8088; E-mail: jdli{at}hei.org.

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