title: Pre-B cell colony-enhancing factor (PBEF/Nampt/visfatin) primes neutrophils for augmented respiratory burst activity through partial assembly of the NADPH oxidase.
abstract: Pre-B cell colony-enhancing factor ([PBEF] also known as Nampt/visfatin) is a pleiotropic 52-kDa cytokine-like molecule whose activity has been implicated in multiple inflammatory disease states. PBEF promotes polymorphonuclear neutrophil (PMN) proinflammatory function by inhibiting constitutive PMN apoptosis. We investigated whether PBEF activates or primes for PMN respiratory burst. We found that although PBEF did not activate respiratory burst on its own, it primed for increased reactive oxygen species generation through the NADPH oxidase. PBEF promoted membrane translocation of cytosolic NADPH oxidase subunits p40 and p47, but not p67, induced p40 phosphorylation on Thr(154), and activated the small GTPase Rac. Priming, translocation, and phosphorylation were dependent on activation of p38 and ERK MAPKs, but not of PI3K. Priming by PBEF occurred independent of its NAD-generating capacity because neither nicotinamide mononucleotide or NAD could recapitulate the effects, and a specific inhibitor of PBEF, APO-866, could not inhibit priming. Taken together, these results demonstrate that PBEF can prime for PMN respiratory burst activity by promoting p40 and p47 translocation to the membrane, and this occurs in a MAPK-dependent fashion.
authors.affiliation: Keenan Research Centre, Li Ka Shing Knowledge Institute, St Michael's Hospital, University of Toronto, Toronto, Ontario M5B 1W8, Canada.
authors.forename: Zeenat
authors.initials: Z
authors.lastname: Malam
authors.forename: Jean
authors.initials: J
authors.lastname: Parodo
authors.forename: Faiza
authors.initials: F
authors.lastname: Waheed
authors.forename: Katalin
authors.initials: K
authors.lastname: Szaszi
authors.forename: Andras
authors.initials: A
authors.lastname: Kapus
authors.forename: John C
authors.initials: JC
authors.lastname: Marshall
mesh_terms: D015153:Blotting, Western; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D019255:NADPH Oxidases / Q000378:metabolism*; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D054409:Nicotinamide Phosphoribosyltransferase / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D021122:Protein Subunits / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D016897:Respiratory Burst; D013912:Threonine / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D005419:Flavonoids; D007093:Imidazoles; D021122:Protein Subunits; D011725:Pyridines; D017382:Reactive Oxygen Species; D013912:Threonine; D019255:NADPH Oxidases; D054409:Nicotinamide Phosphoribosyltransferase; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one