Open AccessTLR2 and TLR4 agonists stimulate unique repertoires of host resistance genes in murine macrophages: interferon-β-dependent signaling in TLR4-mediated responses
Author(s) -
Vladimir Y. Toshchakov,
Bryan W. Jones,
Arnd Lentschat,
Aristóbolo M. Silva,
Pin-Yu Perera,
Karen E. Thomas,
Michael J. Cody,
Shuling Zhang,
Bryan R.G. Williams,
Jennifer Major,
Thomas A. Hamilton,
Matthew J. Fenton,
Stefanie N. Vogel
Publication year - 2003
Publication title -
journal of endotoxin research
Language(s) - English
Resource type - Journals
eISSN - 1743-2839
pISSN - 0968-0519
DOI - 10.1177/09680519030090030501
Subject(s) - tlr2 , autocrine signalling , biology , tlr4 , signal transduction , microbiology and biotechnology , interferon , interferon regulatory factors , signal transducing adaptor protein , stat1 , innate immune system , receptor , immunology , genetics
That TLRs share a common MyD88-dependent signaling pathway which results in the generation of nuclear DNA-binding proteins, such as NF-κB, is a well-accepted paradigm. However, studies from our laboratories and others suggested that TLR4 agonists elicit a more diverse pattern of gene expression in murine macrophages than TLR2 agonists. The data presented show that activation of TLR4 by Escherichia coli LPS results in an MyD88-independent, TIRAP/Mal-dependent signaling pathway that, in turn, leads to early induction of interferon-β (IFN-β). IFN-β , in turn, acts in an autocrine/paracrine fashion on the macrophage to activate STAT1-containing DNA binding complexes that participate in the induction of genes not expressed in response to natural or synthetic TLR2 agonists. These data support the hypothesis that the host response to microbes is controlled by TLRs at two levels: (i) the `sensing' of differences in microbial structures through the TLR extracellular domain; and (ii) signaling pathways that are initiated via interactions through unique intracytoplasmic regions of different TLRs with adaptor proteins.