Abstract
Several components of the canonical pathway of response to lipopolysaccharide (LPS) are required for the EGF-dependent activation of NFκB. Conversely, the ability of Toll-like Receptor 4 (TLR4) to activate NFκB in response to LPS is impaired by down regulating EGF receptor (EGFR) expression or by using the EGFR inhibitor erlotinib. The LYN proto-oncogene (LYN) is required for signaling in both directions. LYN binds to the EGFR upon LPS stimulation, and erlotinib impairs this association. In mice, erlotinib blocks the LPS-induced expression of tumor necrosis factor α (TNFα) and interleukin-6 (IL-6) and ameliorates LPS-induced endotoxity, revealing that EGFR is essential for LPS-induced signaling in vivo.
Keywords:
EGFR; LPS; NFκB; TLR4; erlotinib.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Cell Line
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Cytokines / metabolism
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Epidermal Growth Factor / pharmacology
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ErbB Receptors / metabolism*
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Erlotinib Hydrochloride
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Gene Silencing / drug effects
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Humans
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Lipopolysaccharides / toxicity*
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MAP Kinase Kinase Kinases / metabolism
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Mice
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Myeloid Differentiation Factor 88 / metabolism
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NF-kappa B / metabolism
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Phosphorylation / drug effects
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Protective Agents / pharmacology*
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Proto-Oncogene Mas
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Quinazolines / pharmacology*
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Signal Transduction / drug effects*
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Toll-Like Receptor 4 / metabolism*
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Tumor Necrosis Factor-alpha / pharmacology
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src-Family Kinases / metabolism
Substances
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Cytokines
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Lipopolysaccharides
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MAS1 protein, human
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Myeloid Differentiation Factor 88
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NF-kappa B
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Protective Agents
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Proto-Oncogene Mas
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Quinazolines
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TLR4 protein, human
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Toll-Like Receptor 4
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Tumor Necrosis Factor-alpha
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Epidermal Growth Factor
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Erlotinib Hydrochloride
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ErbB Receptors
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lyn protein-tyrosine kinase
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src-Family Kinases
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MAP Kinase Kinase Kinases
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MAP kinase kinase kinase 7