EGFR kinase activity is required for TLR4 signaling and the septic shock response

EMBO Reports
Saurabh ChattopadhyayGanes C Sen

Abstract

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.

References

Jun 3, 2000·Nature Genetics·N C ArbourD A Schwartz
Aug 30, 2001·Nature Immunology·T HorngR Medzhitov
Jun 11, 2002·Nature Immunology·Yoshinori NagaiKensuke Miyake
Sep 5, 2002·Nature Reviews. Immunology·Michael G KatzeMichael Gale
Apr 8, 2003·Nature Immunology·Marina KaraghiosoffMathias Müller
Jun 25, 2003·Biochemical and Biophysical Research Communications·Shinya SakaguchiTadatsugu Taniguchi
Mar 11, 2004·Proceedings of the National Academy of Sciences of the United States of America·Theresa L GioanniniJerrold P Weiss
Oct 27, 2004·Nature Structural & Molecular Biology·Saumendra N SarkarGanes C Sen
Jan 28, 2006·The Journal of Biological Chemistry·Pearl GrayLuke A J O'Neill
Aug 9, 2006·Cell Research·Dianhua JiangPaul W Noble
Feb 9, 2007·The Journal of Biological Chemistry·Dexing FangZhimin Lu
Mar 30, 2007·The Journal of Biological Chemistry·Andrei E MedvedevStefanie N Vogel
Mar 31, 2007·The Journal of Biological Chemistry·John Hiscott
Apr 26, 2007·Nature Reviews. Immunology·Luke A J O'Neill, Andrew G Bowie
Dec 7, 2007·The Journal of Clinical Investigation·Sizhi Paul GaoJacqueline F Bromberg
Feb 26, 2008·Nature Immunology·Jonathan C KaganRuslan Medzhitov
Apr 3, 2010·The EMBO Journal·Saurabh ChattopadhyayGanes C Sen
Jul 20, 2012·Science Signaling·Michifumi YamashitaGanes C Sen
Dec 4, 2012·The Journal of Clinical Investigation·Bárbara González-TeránGuadalupe Sabio
Nov 19, 2013·The Journal of Immunology : Official Journal of the American Association of Immunologists·Hao JiaoGuochang Hu
Dec 18, 2013·The Journal of Immunology : Official Journal of the American Association of Immunologists·Zhonghua ZhangGurjit K Khurana Hershey
Feb 4, 2014·The Journal of Immunology : Official Journal of the American Association of Immunologists·Kevin ShenderovAlan Sher
Jul 16, 2014·Cytokine & Growth Factor Reviews·Saurabh Chattopadhyay, Ganes C Sen
Oct 11, 2014·Cold Spring Harbor Perspectives in Biology·Surya PandeyShizuo Akira
Apr 1, 2015·Proceedings of the National Academy of Sciences of the United States of America·Janice OrtegaGuo-Min Li

❮ Previous
Next ❯

Citations

Mar 14, 2018·The Journal of Immunology : Official Journal of the American Association of Immunologists·Manoj VeleeparambilGanes C Sen
Dec 2, 2017·The Journal of Cell Biology·Jonathan K L ChanConnie Tam
Nov 15, 2017·Journal of Clinical Pharmacology·Anna E KershBrian P Pollack
Aug 30, 2017·Current Medicinal Chemistry·Sally E Dickinson, Georg T Wondrak
Jul 3, 2019·Nature Immunology·Christopher D ScharerJeremy M Boss
Oct 22, 2016·Respiratory Research·Hitendra S ChandYohannes Tesfaigzi
Jul 10, 2019·IUBMB Life·Tanushree Mukherjee, Kithiganahalli Narayanaswamy Balaji
Nov 29, 2016·Asian Pacific Journal of Tropical Medicine·Wei ChenLin Wu
Feb 6, 2020·Journal of the American Heart Association·Fatimah K KhalafDavid J Kennedy
Jun 11, 2019·Frontiers in Immunology·Aleksandra AntonczykHans A R Bluyssen
Nov 25, 2020·Journal of Cellular Physiology·Bahareh KashaniSeyed H Ghaffari
Feb 14, 2018·Cancer Prevention Research·Karen Blohm-MangoneSally E Dickinson
Jan 27, 2021·Nature Immunology·Tomasz P WypychBenjamin J Marsland
May 18, 2021·Frontiers in Cell and Developmental Biology·Chia-Hsing ShenLi-Chung Hsu
Jun 1, 2021·Frontiers in Pharmacology·Jazlyn P BorgesBenjamin E Steinberg

❮ Previous
Next ❯

Related Concepts

Related Feeds

AKT Pathway

This feed focuses on the AKT serine/threonine kinase, which is an important signaling pathway involved in processes such as glucose metabolism and cell survival.