Proinflammatory Actions of Visfatin/Nicotinamide Phosphoribosyltransferase (Nampt) Involve Regulation of Insulin Signaling Pathway and Nampt Enzymatic Activity

Jacques, Claire; Holzenberger, Martin; Mladenović, Z.; Salvat, Colette; Pecchi, Émilie; Bérenbaum, Francis; Gosset, Marjolaine

doi:10.1074/jbc.m112.350215

Cited by 60 publications

(48 citation statements)

References 51 publications

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“…22,51,52 Using an ad hoc devised assay, 34 we detected NMN production when CLL plasma was incubated with nicotinamide and PRPP ( Figure 2F), with an activity of 1.7 6 0.1 pmol NMN/hour per mL plasma. However, in the absence of added nicotinamide and PRPP, NAMPT activity was undetectable, in line with previous studies.…”

Section: E)mentioning

confidence: 99%

Extracellular nicotinamide phosphoribosyltransferase (NAMPT) promotes M2 macrophage polarization in chronic lymphocytic leukemia

Audrito

Serra

Brusa

et al. 2015

Blood

154

151

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Key Points• CLL lymphocytes show high intracellular and extracellular NAMPT levels, further increased upon activation.• eNAMPT prompts differentiation of CLL monocytes into M2 macrophages that sustain CLL survival and reduce T-cell proliferation.Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in nicotinamide adenine dinucleotide biosynthesis. In the extracellular compartment, it exhibits cytokine-/adipokinelike properties, suggesting that it stands at the crossroad between metabolism and inflammation. Here we show that both intracellular and extracellular NAMPT levels are increased in cells and plasma of chronic lymphocytic leukemia (CLL) patients. The extracellular form (eNAMPT) is produced by CLL lymphocytes upon B-cell receptor, Toll-like receptor, and nuclear factor kB (NF-kB) signaling pathway activation. eNAMPT is important for differentiation of resting monocytes, polarizing them toward tumor-supporting M2 macrophages. These cells express high levels of CD163, CD206, and indoleamine 2,3-dioxygenase and secrete immunosuppressive (interleukin [IL] 10, CC chemokine ligand 18) and tumor-promoting (IL-6, IL-8) cytokines. NAMPT-primed M2 macrophages activate extracellular-regulated kinase 1/2, signal transducer and activator of transcription 3, and NF-kB signaling; promote leukemic cell survival; and reduce T-cell responses. These effects are independent of the enzymatic activity of NAMPT, as inferred from the use of an enzymatically inactive mutant. Overall, these results reveal that eNAMPT is a critical element in the induction of an immunosuppressive and tumor-promoting microenvironment of CLL. (Blood. 2015;125(1):111-123) IntroductionBesides being the first line of defense against pathogens, macrophages orchestrate tissue plasticity and homeostasis. They are classified into classically activated (M1) or alternatively activated (M2) macrophages, reflecting a different functional role. 1 In cancer tissues, macrophages tend to be of the M2 phenotype, acquired and maintained through multiple interactions with tumor cells.2 Evidence indicates that these macrophages enhance tumor progression, mainly through the secretion of chemokines/cytokines that sustain neoplastic the cell proliferation and suppress immune responses. 3,4 Chronic lymphocytic leukemia (CLL) is a disease of mature B cells, which rely on the host environment for progression. [5][6][7] Tumor-host interactions occur predominantly in protected niches in the lymph nodes (LNs) and in the bone marrow, known as proliferation centers. 8,9 Within these areas, CLL cells are in contact with a population of CD681 elements, resembling tumor-associated macrophages. [10][11][12][13] They may be also differentiated in vitro by coculturing peripheral blood monocytes with CLL cells. These so-called nurselike cells (NLCs) protect leukemic cells from apoptosis through multiple interactions regulated by soluble or cell-surface-anchored molecules. 14,15 Leukemic cells play an essential role in driving NLC differentiation, as inferred fr...

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Section: E)mentioning

confidence: 99%

Extracellular nicotinamide phosphoribosyltransferase (NAMPT) promotes M2 macrophage polarization in chronic lymphocytic leukemia

Audrito

Serra

Brusa

et al. 2015

Blood

154

151

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“…In addition, such a treatment resulted in a significant decrease in BMI, HOMA-IR, fasting insulin, and free testosterone, suggesting the possible involvement of visfatin in the pathophysiology of PCOS and its related complications. Many studies also demonstrated that visfatin displayed pro-inflammatory properties and modulated immune functions (Moschen et al 2007, Adya et al 2008, Romacho et al 2009, Fan et al 2011, Jacques et al 2012. Visfatin was reported to induce NF-kB signaling in human endothelial cells and activated MMP-2/9, indicating its possible role in the pathogenesis of PCOS with its pro-inflammatory characteristics (Adya et al 2008).…”

Section: Visfatinmentioning

confidence: 99%

Adipokines in reproductive function: a link between obesity and polycystic ovary syndrome

Chen¹,

Jia²,

Qiao³

et al. 2013

Journal of Molecular Endocrinology

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Polycystic ovary syndrome (PCOS) is the most common endocrinopathy associated with infertility and metabolic disorder in women of reproductive age. Dysfunction of adipose tissue has been implicated in the pathophysiology of PCOS. Increasing evidence shows that the dysregulated expression of adipokines, the secreted products of adipose tissue, plays an important role in the pathology of PCOS. Here, we review the role of several identified adipokines that may act as a link between obesity and PCOS. PCOS also reciprocally influences the profile of adipokines. Insight into the underlying mechanisms will help better understand the pathology of PCOS and identify new therapeutic targets of this syndrome.

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“…Adipokines have attracted much attention as a potential link between inflammation and insulin resistance (61,72). As a recently described adipokine, PBEF has been found to be elevated in acute and chronic inflammatory diseases (29,82) and in diabetes (27,37). Our findings suggest a novel mechanism through which PBEF might mediate insulin resistance by inducing the translocation of the IR from lipid rafts to nonraft domains and, as a consequence, inhibiting signal transduction downstream of the IR.…”

mentioning

confidence: 62%

Pre-B cell colony enhancing factor induces Nampt-dependent translocation of the insulin receptor out of lipid microdomains in A549 lung epithelial cells

Peng

Jia

Parodo

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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. Pre-B cell colony enhancing factor induces Nampt-dependent translocation of the insulin receptor out of lipid microdomains in A549 lung epithelial cells. Am J Physiol Endocrinol Metab 308: E324 -E333, 2015. First published December 17, 2014 doi:10.1152/ajpendo.00006.2014.-Pre-B cell colony-enhancing factor (PBEF) is a highly conserved pleiotropic protein reported to be an alternate ligand for the insulin receptor (IR). We sought to clarify the relationship between PBEF and insulin signaling by evaluating the effects of PBEF on the localization of the IR␤ chain to lipid rafts in A549 epithelial cells. We isolated lipid rafts from A549 cells and detected the IR by immunoprecipitation from raft fractions or whole cell lysates. Cells were treated with rPBEF, its enzymatic product nicotinamide adenine dinucleotide (NAD), or the Nampt inhibitor daporinad to study the effect of PBEF on IR␤ movement. We used coimmunoprecipitation studies in cells transfected with PBEF and IR␤ constructs to detect interactions between PBEF, the IR␤, and caveolin-1 (Cav-1). PBEF was present in both lipid raft and nonraft fractions, whereas the IR was found only in lipid raft fractions of resting A549 cells. The IR-, PBEF-, and Cav-1-coimmunoprecipitated rPBEF treatment resulted in the movement of IR␤-and tyrosine-phosphorylated Cav-1 from lipid rafts to nonrafts, an effect that could be blocked by daporinad, suggesting that this effect was facilitated by the Nampt activity of PBEF. The addition of PBEF to insulin-treated cells resulted in reduced Akt phosphorylation of both Ser 473 and Thr 308 . We conclude that PBEF can inhibit insulin signaling through the IR by Nampt-dependent promotion of IR translocation into the nonraft domains of A549 epithelial cells. PBEFinduced alterations in the spatial geometry of the IR provide a mechanistic explanation for insulin resistance in inflammatory states associated with upregulation of PBEF.pre-B cell colony-enhancing factor; nicotinamide phosphoribosyl transferase; lipid rafts; insulin; insulin receptor; caveolin-1; signaling; phosphorylation CELLULAR RESPONSES TO STIMULI from the microenvironment are dependent upon the capacity of proteins in the cell membrane to aggregate and dissociate, and so they create multiprotein platforms that initiate intracellular signaling and lead to gene expression or repression within the nucleus. How these dynamic interactions are facilitated is incompletely understood. Lipid rafts are small, self-organizing dynamic membrane domains enriched in cholesterol, sphingolipid, and other proteins that are hypothesized to contribute to protein-protein interactions within the cell membrane (64,66,66), although whether lipids per se mediate protein sorting or whether protein localization within the membrane is a function of actin associating with membrane sphingolipids remains controversial (35).Caveolae represent a particular type of lipid raft that appears as a flask-shaped invagination of the cell surface (2). The formation and maintenance of caveolae depends on the pre...

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Proinflammatory Actions of Visfatin/Nicotinamide Phosphoribosyltransferase (Nampt) Involve Regulation of Insulin Signaling Pathway and Nampt Enzymatic Activity

Cited by 60 publications

References 51 publications

Extracellular nicotinamide phosphoribosyltransferase (NAMPT) promotes M2 macrophage polarization in chronic lymphocytic leukemia

Extracellular nicotinamide phosphoribosyltransferase (NAMPT) promotes M2 macrophage polarization in chronic lymphocytic leukemia

Adipokines in reproductive function: a link between obesity and polycystic ovary syndrome

Pre-B cell colony enhancing factor induces Nampt-dependent translocation of the insulin receptor out of lipid microdomains in A549 lung epithelial cells

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