Toll-like receptor 4 signalling: new perspectives on a complex signal-transduction problem.
We previously reported that Toll-like receptor-2 (TLR2) agonists induce expression of a more limited repertoire of pro-inflammatory genes than TLR4 agonists. Murine macrophages stimulated with the TLR4 agonist, Escherichia coli lipopolysaccharide, induced signal transducer and activator of transcription 1 ('STAT1') tyrosine phosphorylation that was secondary to the autocrine/paracrine action of interferon (IFN)-beta, an immediate early gene. In contrast, TLR2 agonists failed to activate IFN-beta gene expression. TLR4-induced IFN-beta mRNA was found to be MyD88- and PKR (double-stranded RNA-dependent protein kinase)-independent, but TIRAP (Toll/interleukin-1 receptor domain-containing adapter protein)/Mal (MyD88-adapter-like)-dependent. In the present paper, we outline the recent controversy over the role of TIRAP/Mal in TLR2 and TLR4 signalling in the context of the current molecular tools used for such studies. Collectively, our findings provide the first mechanistic basis for differential patterns of gene expression activated by TLR4 and TLR2 agonists.
Vogel
S N
SN
Department of Microbiology and Immunology, and Department of Medicine, University of Maryland, Baltimore, 655 W. Baltimore Street 13-009, Baltimore, MD 21201, USA. svogel@som.umaryland.edu
Fenton
M
M
D000818:Animals; D004926:Escherichia coli; D005786:Gene Expression Regulation / Q000187:drug effects; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D008954:Models, Biological; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors