EGFR kinase activity is required for TLR4 signaling and the septic shock response.
Mammalian Toll-like receptors (TLR) recognize microbial products and elicit transient immune responses that protect the infected host from disease. TLR4--which signals from both plasma and endosomal membranes--is activated by bacterial lipopolysaccharides (LPS) and induces many cytokine genes, the prolonged expression of which causes septic shock in mice. We report here that the expression of some TLR4-induced genes in myeloid cells requires the protein kinase activity of the epidermal growth factor receptor (EGFR). EGFR inhibition affects TLR4-induced responses differently depending on the target gene. The induction of interferon-β (IFN-β) and IFN-inducible genes is strongly inhibited, whereas TNF-α induction is enhanced. Inhibition is specific to the IFN-regulatory factor (IRF)-driven genes because EGFR is required for IRF activation downstream of TLR--as is IRF co-activator β-catenin--through the PI3 kinase/AKT pathway. Administration of an EGFR inhibitor to mice protects them from LPS-induced septic shock and death by selectively blocking the IFN branch of TLR4 signaling. These results demonstrate a selective regulation of TLR4 signaling by EGFR and highlight the potential use of EGFR inhibitors to treat septic shock syndrome.
Department of Molecular Genetics, Lerner Research Institute Cleveland Clinic, Cleveland, OH, USA.
Saurabh
S
Chattopadhyay
Department of Molecular Genetics, Lerner Research Institute Cleveland Clinic, Cleveland, OH, USA.
Manoj
M
Veleeparambil
Department of Molecular Genetics, Lerner Research Institute Cleveland Clinic, Cleveland, OH, USA.
Darshana
D
Poddar
Department of Molecular Genetics, Lerner Research Institute Cleveland Clinic, Cleveland, OH, USA.
Samar
S
Abdulkhalek
Department of Molecular Genetics, Lerner Research Institute Cleveland Clinic, Cleveland, OH, USA.
Sudip K
SK
Bandyopadhyay
Department of Molecular Genetics, Lerner Research Institute Cleveland Clinic, Cleveland, OH, USA.
Volker
V
Fensterl
Department of Molecular Genetics, Lerner Research Institute Cleveland Clinic, Cleveland, OH, USA seng@ccf.org.
Ganes C
GC
Sen
D000818:Animals; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000077156:Gefitinib; D050835:Interferon Regulatory Factors / Q000378:metabolism; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000008:administration & dosage; D051379:Mice; D046228:Microarray Analysis; D022423:Myeloid Cells / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D000067996:RAW 264.7 Cells; D012772:Shock, Septic / Q000378:metabolism* / Q000517:prevention & control / Q000628:therapy; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D050835:Interferon Regulatory Factors; D008070:Lipopolysaccharides; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D016899:Interferon-beta; D019869:Phosphatidylinositol 3-Kinases; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D000077156:Gefitinib
AKT; EGFR; IRF; PI3 Kinase; TLR; septic shock; β‐catenin