title: Erlotinib protects against LPS-induced endotoxicity because TLR4 needs EGFR to signal.
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.
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; starkg@ccf.org des@ccf.org.
authors.forename: Sarmishtha
authors.initials: S
authors.lastname: De
authors.affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195;
authors.forename: Hao
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Nutrition, Case Western Reserve University School of Medicine, Cleveland, OH 44106.
authors.forename: David
authors.initials: D
authors.lastname: DeSantis
authors.affiliation: Department of Nutrition, Case Western Reserve University School of Medicine, Cleveland, OH 44106.
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Croniger
authors.affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195;
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; starkg@ccf.org des@ccf.org.
authors.forename: George R
authors.initials: GR
authors.lastname: Stark
mesh_terms: D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D008070:Lipopolysaccharides / Q000633:toxicity*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D020011:Protective Agents / Q000494:pharmacology*; D000090063:Proto-Oncogene Mas; D011799:Quinazolines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019061:src-Family Kinases / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D016207:Cytokines; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D008070:Lipopolysaccharides; D020930:MAP Kinase Kinase Kinases; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D020011:Protective Agents; D000090063:Proto-Oncogene Mas; D011799:Quinazolines; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D019061:src-Family Kinases; D000099151:MAP Kinase Kinase Kinase 7; C000715470:MAS1 protein, human; C495345:TLR4 protein, human; C060902:lyn protein-tyrosine kinase
keywords: EGFR; LPS; NFκB; TLR4; erlotinib