Pre-B Cell Colony-Enhancing Factor (PBEF/Nampt/Visfatin) Primes Neutrophils for Augmented Respiratory Burst Activity through Partial Assembly of the NADPH Oxidase

Malam, Zeenat; Parodo, Jean; Waheed, Faiza; Szászi, Katalin; Kapùs, András; Marshall, John C.

doi:10.4049/jimmunol.1003706

Cited by 26 publications

(14 citation statements)

References 57 publications

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“…Li et al36 also reported that extracellular PBEF protected macrophages from endoplasmic reticulum stress-induced apoptosis by activating an IL6/STAT3 signaling pathway via a non-enzymatic mechanism of NAMPT. Malam et al37 demonstrated that priming for neutrophil respiratory burst by PBEF (NAMPT) occurred independently of its NAD-generating capacity because neither NM nor NAD could recapitulate the effects and, furthermore, that FK866 could not inhibit priming. Based on these observations, we posit that MC4 may have a higher binding affinity to NAMPT than FK866, which leads to a more severe distorted conformation, resulting in structural constraints not favorable to the interaction of NAMPT with its elusive receptor or other key proteins.…”

Section: Discussionmentioning

confidence: 99%

MC-PPEA as a new and more potent inhibitor of CLP-induced sepsis and pulmonary inflammation than FK866

Huang

Lee

Sadrerafi

et al. 2017

DDDT

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Our previous study indicated that overexpression of nicotinamide phosphoribosyltransferase (NAMPT) aggravated acute lung injury, while knockdown of NAMPT expression attenuated ventilator-induced lung injury. Recently, we found that meta-carborane-butyl-3-(3-pyridinyl)-2E-propenamide (MC-PPEA, MC4), in which the benzoylpiperidine moiety of FK866 has been replaced by a carborane, displayed a 100-fold increase in NAMPT inhibition over FK866. Here, we determined the effects of MC4 and FK866 on cecal ligation and puncture (CLP) surgery-induced sepsis in C57BL/6J mice. MC4 showed stronger inhibitory effects than FK866 on CLP-induced mortality, serum tumor necrosis factor α (TNFα) levels, pulmonary myeloperoxidase activity, alveolar injury, and interleukin 6 and interleukin1β messenger RNA levels. In vitro cell permeability and electric cell–substrate impedance sensing assays demonstrated that MC4 inhibited TNFα- and thrombin-mediated pulmonary endothelial cell permeability better than FK866. MC4 also exerted more potent effects than FK866, at concentrations as low as 0.3 nM, to attenuate TNFα-mediated intracellular cytokine expression, nicotinamide adenine dinucleotide (NAD+) and its reduced form NADH levels, and nuclear factor kappa B p65 phosphorylation and nuclear translocation in A549 cells. Our results strongly suggest that the newly developed MC4 is a more potent suppressor of CLP-induced pulmonary inflammation and sepsis than FK866, with potential clinical application as a new treatment agent for sepsis and inflammation.

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Section: Discussionmentioning

confidence: 99%

MC-PPEA as a new and more potent inhibitor of CLP-induced sepsis and pulmonary inflammation than FK866

Huang

Lee

Sadrerafi

et al. 2017

DDDT

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“…A more recent study has shown that NAMPT primes neutrophils for augmented respiratory burst through the generation of reactive oxygen species via NADPH oxidase [80].…”

Section: Nampt Expression In Inflammatory Cellsmentioning

confidence: 99%

PBEF/NAMPT/Visfatin: A Promising Drug Target For Treating Rheumatoid Arthritis?

2012

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NAMPT, also known as pre-B-cell colony-enhancing factor and visfatin, has been proposed to be involved in preventing apoptosis in cancer cells and, as such, has received a great deal of attention in recent years and stimulated the development to specific inhibitors for treating cancer. The role of NAMPT inhibitors as potential therapeutic agents for other diseases has not been studied extensively. Here, we describe their applicability for treating rheumatoid arthritis. We summarize current knowledge of NAMPT expression in healthy and diseased tissues, thereafter, we focus on pathological mechanisms relevant to rheumatoid arthritis that involve the NAMPT pathway and review the current status of NAMPT inhibitors being evaluated in clinical trials.

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“…A potential interaction between PBEF and insulin signaling was first reported by Fukuhara et al (15), although this report was subsequently retracted (16). Others have shown that PBEF can induce the activation of IR␤ (31), Akt (54), ERK, and p38 (41), although the capacity of PBEF to activate IR␤ (54) and Akt (75) has been challenged. Using A549 lung epithelial cells, we found that PBEF itself could not induce the phosphorylation of IR␤ nor activate Akt.…”

mentioning

confidence: 94%

“…First, as a Nampt, PBEF catalyzes the rate-limiting step in a salvage pathway of nicotinamide adenine dinucleotide (NAD) biosynthesis (55). Second, it has proinflammatory activity as an extracellular cytokine-like molecule that is involved in acute and chronic inflammation (38,45), inhibits neutrophil apoptosis (29), and primes neutrophil respiratory burst (41). The third and most controversial function of PBEF is as an alternate ligand for the IR (15).…”

mentioning

confidence: 99%

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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Pre-B Cell Colony-Enhancing Factor (PBEF/Nampt/Visfatin) Primes Neutrophils for Augmented Respiratory Burst Activity through Partial Assembly of the NADPH Oxidase

Cited by 26 publications

References 57 publications

MC-PPEA as a new and more potent inhibitor of CLP-induced sepsis and pulmonary inflammation than FK866

MC-PPEA as a new and more potent inhibitor of CLP-induced sepsis and pulmonary inflammation than FK866

PBEF/NAMPT/Visfatin: A Promising Drug Target For Treating Rheumatoid Arthritis?

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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