Cutting edge: anthrax lethal toxin inhibits activation of IFN-regulatory factor 3 by lipopolysaccharide.
IFN-regulatory factor 3 (IRF3) is known to participate in the transcriptional induction of chemokines and cytokines, including IFNs, as a result of viral or bacterial infection. In this study, we demonstrate that the LPS-mediated activation of IRF3 and subsequent induction of chemokine genes or IRF3-responsive reporter constructs are inhibited after exposure of human or murine macrophages to the Bacillus anthracis toxin lethal factor. The inhibitory effect is caused by interference with the activation of the stress-activated protein kinase, p38, due to a proteolytic cleavage of mitogen-activated protein kinase kinase 6, and can be overcome by the ectopic expression of a cleavage-resistant mutant of mitogen-activated protein kinase kinase 6 or a constitutively active IRF3. The lethal factor-mediated inhibition of IRF3 activation and subsequent cytokine production through bacterial membrane components offers Bacillus anthracis an efficient mechanism to evade the innate immune response.
Dang
Oanh
O
Department of Biology, Division of Biological Sciences and UCSD Cancer Center, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093.
Navarro
Lorena
L
Anderson
Keith
K
David
Michael
M
D000818:Animals; D000942:Antigens, Bacterial; D001408:Bacillus anthracis / Q000276:immunology* / Q000472:pathogenicity; D001427:Bacterial Toxins / Q000494:pharmacology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D018946:Chemokine CCL5 / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D050838:Interferon Regulatory Factor-3; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D048371:MAP Kinase Kinase 3; D048669:MAP Kinase Kinase 6; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D018345:Mice, Knockout; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D016297:Mutagenesis, Site-Directed; D021122:Protein Subunits / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases
D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D018946:Chemokine CCL5; D004268:DNA-Binding Proteins; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; C494233:Irf3 protein, mouse; D008070:Lipopolysaccharides; D021122:Protein Subunits; D014157:Transcription Factors; C030325:anthrax toxin; D011505:Protein-Tyrosine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048371:MAP Kinase Kinase 3; D048669:MAP Kinase Kinase 6; C482530:MAP2K3 protein, human; C482566:MAP2K6 protein, human; C482531:Map2k3 protein, mouse; C482567:Map2k6 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases