Proinflammatory Actions of Visfatin/Nicotinamide Phosphoribosyltransferase (Nampt) Involve Regulation of Insulin Signaling Pathway and Nampt Enzymatic Activity
Proinflammatory Actions of Visfatin/Nicotinamide Phosphoribosyltransferase (Nampt) Involve Regulation of Insulin Signaling Pathway and Nampt Enzymatic Activity
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DOI：
10.1074/jbc.m112.350215
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发表时间：
2012-04-27
影响因子：
4.8
通讯作者：
Gosset, Marjolaine
中科院分区：
文献类型：
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作者：
Jacques, Claire;Holzenberger, Martin;Gosset, Marjolaine
Visfatin(也称为前B细胞集落增强因子(PBEF)或烟酰胺磷酸核糖基转移酶(NAMPT))是一种多效性介质，作用于包括骨关节炎在内的许多炎症过程。Visfatin既具有导致NAD合成的细胞内酶活性(烟酰胺磷酸核糖基转移酶，NAMPT)，又通过与其假设的受体结合而发挥细胞因子功能。我们最近报道了内脂素在软骨细胞前列腺素E-2(PGE(2))合成中的作用。在这里，我们的目的是通过探索胰岛素受体(IR)信号通路和NAMPT活性来表征参与这一反应的信号通路。IR在人和小鼠软骨细胞中表达，内脂素在小鼠软骨细胞中激活Akt磷酸化。用siRNA阻断IR的表达或用羟基-2-萘甲基膦酸三乙酰氧甲酯(HNMPA-(AM)(3))抑制剂阻断IR的表达可减少内脂素诱导的软骨细胞PGE(2)的释放。此外，内脂素诱导的IGF-1R(-/-)软骨细胞比IGF-1R(+/+)细胞释放更高浓度的PGE(2)，这一发现与阻断IGF-1R的抗体证实了这一发现。使用RT-PCR，我们发现内脂素不调节IR的表达，而且胰岛素释放的增加也不太可能参与其中，因为胰岛素不能增加PGE(2)的释放。用APO866抑制剂抑制NAMPT活性会逐渐减少PGE(2)的释放，而外源烟酰胺的加入会增加PGE(2)的释放。我们得出结论，内脂素在软骨细胞中的促炎作用涉及IR信号通路的调节，可能是通过控制NAMPT酶的活性。
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.