Vav proteins control MyD88-dependent oxidative burst.
The importance of reactive oxygen intermediate (ROI) production in antimicrobial responses is demonstrated in human patients who suffer from chronic granulomatous disease (CGD) due to defective NADPH oxidase function. Exactly how bacterial products activating Toll-like receptors (TLRs) induce oxidative burst is unknown. Here, we identify the Vav family of Rho guanine nucleotide exchange factors (GEFs) as critical mediators of LPS-induced MyD88-dependent activation of Rac2, NADPH oxidase, and ROI production using mice deficient in Vav1, Vav2, and Vav3. Vav proteins are also required for p38 MAPK activation and for normal regulation of proinflammatory cytokine production, but not for other MyD88-controlled effector pathways such as those involving JNK, COX2, or iNOS and the production of reactive nitrogen intermediates (RNIs). Thus, our data indicate that Vav specifically transduces a subset of signals emanating from MyD88.
Miletic
Ana V
AV
Department of Pathology and Immunology, Washington University School of Medicine and Siteman Cancer Center, 660 S. Euclid Avenue, St. Louis, MO 63110, USA.
Graham
Daniel B
DB
Montgrain
Vivianne
V
Fujikawa
Keiko
K
Kloeppel
Tracie
T
Brim
Karry
K
Weaver
Brian
B
Schreiber
Robert
R
Xavier
Ramnik
R
Swat
Wojciech
W
D000818:Animals; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D006105:Granulomatous Disease, Chronic / Q000201:enzymology / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D048670:MAP Kinase Kinase 4 / Q000276:immunology; D008264:Macrophages / Q000201:enzymology / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009097:Multienzyme Complexes / Q000172:deficiency / Q000276:immunology; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000276:immunology*; D009247:NADH, NADPH Oxidoreductases / Q000172:deficiency / Q000276:immunology; D052247:Nitric Oxide Synthase Type II / Q000276:immunology; D051567:Proto-Oncogene Proteins c-vav / Q000172:deficiency / Q000276:immunology*; D017382:Reactive Oxygen Species / Q000276:immunology*; D016897:Respiratory Burst / Q000187:drug effects / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D020744:rac GTP-Binding Proteins / Q000276:immunology; D000097766:RAC2 GTP-Binding Protein
D051546:Cyclooxygenase 2; D016207:Cytokines; D008070:Lipopolysaccharides; D048670:MAP Kinase Kinase 4; D009097:Multienzyme Complexes; D053594:Myeloid Differentiation Factor 88; D009247:NADH, NADPH Oxidoreductases; D052247:Nitric Oxide Synthase Type II; D051567:Proto-Oncogene Proteins c-vav; D017382:Reactive Oxygen Species; D020744:rac GTP-Binding Proteins; D000097766:RAC2 GTP-Binding Protein; C507780:Myd88 protein, mouse; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse; C023107:NADH oxidase