TLR4, but not TLR2, mediates IFN-beta-induced STAT1alpha/beta-dependent gene expression in macrophages.
Toll-like receptor 2 (TLR2) agonists induce a subset of TLR4-inducible proinflammatory genes, which suggests the use of differential signaling pathways. Murine macrophages stimulated with the TLR4 agonist Escherichia coli lipopolysaccharide (LPS), but not with TLR2 agonists, induced phosphorylation of signal transducer and activator of transcription 1alpha (STAT1alpha) and STAT1beta, which was blocked by antibodies to interferon beta (IFN-beta) but not IFN-alpha. All TLR2 agonists poorly induced IFN-beta, which is encoded by an immediate early LPS-inducible gene. Thus, the failure of TLR2 agonists to induce STAT1-dependent genes resulted, in part, from their inability to express IFN-beta. TLR4-induced IFN-beta mRNA was MyD88- and PKR (double-stranded RNA-dependent protein kinase)-independent, but TIRAP (Toll-interleukin 1 receptor domain-containing adapter protein)-dependent. Together, these findings provide the first mechanistic basis for differential patterns of gene expression activated by TLR4 and TLR2 agonists.
Toshchakov
Vladimir
V
Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
Jones
Bryan W
BW
Perera
Pin-Yu
PY
Thomas
Karen
K
Cody
M Joshua
MJ
Zhang
Shuling
S
Williams
Bryan R G
BR
Major
Jennifer
J
Hamilton
Thomas A
TA
Fenton
Matthew J
MJ
Vogel
Stefanie N
SN
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism*; D029721:Drosophila Proteins; D004789:Enzyme Activation; D004926:Escherichia coli; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D050832:Interferon-Stimulated Gene Factor 3; D016899:Interferon-beta / Q000235:genetics*; D007375:Interleukin-1 / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000819:agonists / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018945:Monocyte Chemoattractant Proteins / Q000235:genetics; D053594:Myeloid Differentiation Factor 88; D019001:Nitric Oxide Synthase / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D010766:Phosphorylation; D012333:RNA, Messenger; D011956:Receptors, Cell Surface / Q000819:agonists / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D050794:STAT1 Transcription Factor; D015398:Signal Transduction; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; C491224:Ccl12 protein, mouse; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D050832:Interferon-Stimulated Gene Factor 3; D007375:Interleukin-1; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D018945:Monocyte Chemoattractant Proteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D017472:Receptors, Interleukin-1; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; C499045:TIRAP protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D015534:Trans-Activators; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; C079868:gamma interferon activation factor; D016899:Interferon-beta; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D020928:Mitogen-Activated Protein Kinases