title: Proinflammatory actions of visfatin/nicotinamide phosphoribosyltransferase (Nampt) involve regulation of insulin signaling pathway and Nampt enzymatic activity.
abstract: Visfatin (also termed pre-B-cell colony-enhancing factor (PBEF) or nicotinamide phosphoribosyltransferase (Nampt)) is a pleiotropic mediator acting on many inflammatory processes including osteoarthritis. Visfatin exhibits both an intracellular enzymatic activity (nicotinamide phosphoribosyltransferase, Nampt) leading to NAD synthesis and a cytokine function via the binding to its hypothetical receptor. We recently reported the role of visfatin in prostaglandin E(2) (PGE(2)) synthesis in chondrocytes. Here, our aim was to characterize the signaling pathways involved in this response in exploring both the insulin receptor (IR) signaling pathway and Nampt activity. IR was expressed in human and murine chondrocytes, and visfatin triggered Akt phosphorylation in murine chondrocytes. Blocking IR expression with siRNA or activity using the hydroxy-2-naphthalenyl methyl phosphonic acid tris acetoxymethyl ester (HNMPA-(AM)(3)) inhibitor diminished visfatin-induced PGE(2) release in chondrocytes. Moreover, visfatin-induced IGF-1R(-/-) chondrocytes released higher concentration of PGE(2) than IGF-1R(+/+) cells, a finding confirmed with an antibody that blocked IGF-1R. Using RT-PCR, we found that visfatin did not regulate IR expression and that an increased insulin release was also unlikely to be involved because insulin was unable to increase PGE(2) release. Inhibition of Nampt activity using the APO866 inhibitor gradually decreased PGE(2) release, whereas the addition of exogenous nicotinamide increased it. We conclude that the proinflammatory actions of visfatin in chondrocytes involve regulation of IR signaling pathways, possibly through the control of Nampt enzymatic activity.
authors.affiliation: UR4, Pierre and Marie Curie University, 75252 Paris, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Jacques
authors.forename: Martin
authors.initials: M
authors.lastname: Holzenberger
authors.forename: Zvezdana
authors.initials: Z
authors.lastname: Mladenovic
authors.forename: Colette
authors.initials: C
authors.lastname: Salvat
authors.forename: Emilie
authors.initials: E
authors.lastname: Pecchi
authors.forename: Francis
authors.initials: F
authors.lastname: Berenbaum
authors.forename: Marjolaine
authors.initials: M
authors.lastname: Gosset
mesh_terms: D000178:Acrylamides / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D019902:Chondrocytes / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009281:Naphthalenes / Q000494:pharmacology; D054409:Nicotinamide Phosphoribosyltransferase / Q000235:genetics / Q000378:metabolism*; D063065:Organophosphonates / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis / Q000235:genetics; D011972:Receptor, Insulin / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction
chemical_list: D000178:Acrylamides; D016207:Cytokines; D007328:Insulin; C480543:N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide; D009281:Naphthalenes; D063065:Organophosphonates; D010880:Piperidines; C060935:(hydroxy-2-naphthalenylmethyl)phosphonic acid; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human; C495867:nicotinamide phosphoribosyltransferase, mouse; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D015232:Dinoprostone