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Erlotinib protects against LPS-induced endotoxicity because TLR4 needs EGFR to signal.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2015 Aug 04; Vol. 112 (31), pp. 9680-5. Date of Electronic Publication: 2015 Jul 20. - Publication Year :
- 2015
-
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.
- Subjects :
- Animals
Cell Line
Cytokines metabolism
Epidermal Growth Factor pharmacology
Erlotinib Hydrochloride
Gene Silencing drug effects
Humans
MAP Kinase Kinase Kinases metabolism
Mice
Myeloid Differentiation Factor 88 metabolism
NF-kappa B metabolism
Phosphorylation drug effects
Proto-Oncogene Mas
Tumor Necrosis Factor-alpha pharmacology
src-Family Kinases metabolism
ErbB Receptors metabolism
Lipopolysaccharides toxicity
Protective Agents pharmacology
Quinazolines pharmacology
Signal Transduction drug effects
Toll-Like Receptor 4 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 112
- Issue :
- 31
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 26195767
- Full Text :
- https://doi.org/10.1073/pnas.1511794112