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

• Published in: The Journal of biological chemistry 2005-10, Vol.280 (43), p.36185-36194
• Main Authors: Mikami, Fumi, Gu, He, Jono, Hirofumi, Andalibi, Ali, Kai, Hirofumi, Li, Jian-Dong
• Format: Article
• Language: English
• Subjects: Animals; Blotting, Western; Cell Adhesion; Cell Differentiation; Cell Movement; Down-Regulation; Enzyme-Linked Immunosorbent Assay; Epidermal Growth Factor - metabolism; Epithelial Cells - cytology; ErbB Receptors - metabolism; ErbB Receptors - physiology; Gene Expression Regulation; Haemophilus influenzae; Haemophilus influenzae - metabolism; HeLa Cells; Humans; Immune System; Immunoprecipitation; MAP Kinase Kinase 3 - metabolism; MAP Kinase Kinase 6 - metabolism; MAP Kinase Signaling System; Mice; Mice, Inbred BALB C; Models, Biological; p38 Mitogen-Activated Protein Kinases - metabolism; Phosphorylation; Plasmids - metabolism; Recombinant Proteins - chemistry; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; RNA, Messenger - metabolism; Signal Transduction; src-Family Kinases - metabolism; Time Factors; Toll-Like Receptor 2 - metabolism; Transfection
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M503941200

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 α/β 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.