title: Vav proteins control MyD88-dependent oxidative burst.
abstract: 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.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine and Siteman Cancer Center, 660 S. Euclid Avenue, St. Louis, MO 63110, USA.
authors.forename: Ana V
authors.initials: AV
authors.lastname: Miletic
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Graham
authors.forename: Vivianne
authors.initials: V
authors.lastname: Montgrain
authors.forename: Keiko
authors.initials: K
authors.lastname: Fujikawa
authors.forename: Tracie
authors.initials: T
authors.lastname: Kloeppel
authors.forename: Karry
authors.initials: K
authors.lastname: Brim
authors.forename: Brian
authors.initials: B
authors.lastname: Weaver
authors.forename: Robert
authors.initials: R
authors.lastname: Schreiber
authors.forename: Ramnik
authors.initials: R
authors.lastname: Xavier
authors.forename: Wojciech
authors.initials: W
authors.lastname: Swat
mesh_terms: 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
chemical_list: 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