title: Pharmacological inhibition of nicotinamide phosphoribosyltransferase/visfatin enzymatic activity identifies a new inflammatory pathway linked to NAD.
abstract: Nicotinamide phosphoribosyltransferase (NAMPT), also known as visfatin, is the rate-limiting enzyme in the salvage pathway of NAD biosynthesis from nicotinamide. Since its expression is upregulated during inflammation, NAMPT represents a novel clinical biomarker in acute lung injury, rheumatoid arthritis, and Crohn's disease. However, its role in disease progression remains unknown. We report here that NAMPT is a key player in inflammatory arthritis. Increased expression of NAMPT was confirmed in mice with collagen-induced arthritis, both in serum and in the arthritic paw. Importantly, a specific competitive inhibitor of NAMPT effectively reduced arthritis severity with comparable activity to etanercept, and decreased pro-inflammatory cytokine secretion in affected joints. Moreover, NAMPT inhibition reduced intracellular NAD concentration in inflammatory cells and circulating TNFalpha levels during endotoxemia in mice. In vitro pharmacological inhibition of NAMPT reduced the intracellular concentration of NAD and pro-inflammatory cytokine secretion by inflammatory cells. Thus, NAMPT links NAD metabolism to inflammatory cytokine secretion by leukocytes, and its inhibition might therefore have therapeutic efficacy in immune-mediated inflammatory disorders.
authors.affiliation: Service of Rheumatology, Department of Medicine, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Busso
authors.forename: Mahir
authors.initials: M
authors.lastname: Karababa
authors.forename: Massimo
authors.initials: M
authors.lastname: Nobile
authors.forename: Aline
authors.initials: A
authors.lastname: Rolaz
authors.forename: Frédéric
authors.initials: F
authors.lastname: Van Gool
authors.forename: Mara
authors.initials: M
authors.lastname: Galli
authors.forename: Oberdan
authors.initials: O
authors.lastname: Leo
authors.forename: Alexander
authors.initials: A
authors.lastname: So
authors.forename: Thibaut
authors.initials: T
authors.lastname: De Smedt
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000201:enzymology; D003094:Collagen / Q000008:administration & dosage; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D007249:Inflammation / Q000201:enzymology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009243:NAD / Q000378:metabolism*; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D015854:Up-Regulation
chemical_list: D004791:Enzyme Inhibitors; D014409:Tumor Necrosis Factor-alpha; D009243:NAD; D003094:Collagen; D054409:Nicotinamide Phosphoribosyltransferase