Inhibition of mitogen-activated protein kinase signalling by Bacillus anthracis lethal toxin causes destabilization of interleukin-8 mRNA.
Bacillus anthracis must overcome host innate immune defences to establish a systemic anthrax infection. This is facilitated in part by lethal toxin (LT), a secreted virulence factor that consists of a cell-binding moiety, protective antigen (PA), and an enzymatic moiety, lethal factor (LF). PA binds cells through protein receptors and mediates the delivery of LF to the cytosol. LF is a protease that cleaves amino-terminal fragments from mitogen-activated protein kinase kinases (MAPKKs), preventing phosphorylation of their downstream targets. Here we report that LT reduces the amount of interleukin (IL)-8 produced and secreted by human endothelial cells. The reduction of IL-8 levels by LT was not attributable to reduced expression from the IL-8 promoter, but resulted from destabilization of IL-8 mRNA. Destabilization by LT was mediated through the 3' untranslated region of the IL-8 transcript and could be mimicked by pharmacological inhibitors of MAPK pathways. LT diminished the induction of IL-8 mRNA and protein by lipopolysaccharide, indicating that the toxin can impair the ability of these cells to initiate an immune response. Destabilization of a cytokine transcript represents a new interference strategy used by either a bacterial or viral pathogen to reduce cytokine expression and may help B. anthracis to evade host immune defences.
Batty
Sarah
S
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
Chow
Edith M C
EM
Kassam
Altaf
A
Der
Sandy D
SD
Mogridge
Jeremy
J
D020413:3' Untranslated Regions; D000873:Anthracenes / Q000494:pharmacology; D000942:Antigens, Bacterial / Q000502:physiology*; D001408:Bacillus anthracis / Q000378:metabolism*; D001427:Bacterial Toxins; D002070:Butadienes / Q000494:pharmacology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D009570:Nitriles / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011725:Pyridines / Q000494:pharmacology; D020871:RNA Stability; D012333:RNA, Messenger / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction
D020413:3' Untranslated Regions; D000873:Anthracenes; D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D002070:Butadienes; D007093:Imidazoles; D016209:Interleukin-8; D008070:Lipopolysaccharides; D009570:Nitriles; D011725:Pyridines; D012333:RNA, Messenger; C113580:U 0126; C030325:anthrax toxin; C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole