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Originally published online as doi:10.1189/jlb.0807581 on February 5, 2008

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(Journal of Leukocyte Biology. 2008;83:804-816.)
© 2008 by Society for Leukocyte Biology

Pre-B cell colony-enhancing factor (PBEF)/visfatin: a novel mediator of innate immunity

Tracy Luk, Zeenat Malam and John C. Marshall1

Departments of Surgery and Critical Care Medicine and the Li Ka Shing Knowledge Institute, St. Michael’s Hospital, University of Toronto, Ontario, Canada

1 Correspondence: St. Michael’s Hospital, 4th Floor Bond Wing, Rm. 4-007, 30 Bond Street, Toronto, Ontario, M5B 1W8, Canada. E-mail: marshallj{at}smh.toronto.on.ca


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ABSTRACT
 
Pre-B cell colony-enhancing factor (PBEF), also known as visfatin, is a highly conserved, 52-kDa protein found in living species from bacteria to humans. Originally a curiosity identified serendipitously in microarray studies but having no obvious functional importance, PBEF has now been shown to exert three distinct activities of central importance to cellular energetics and innate immunity. Within the cell, PBEF functions as a nicotinamide phosphoribosyl transferase, the rate-limiting step in a salvage pathway of nicotinamide adenine dinucleotide (NAD) biosynthesis. By virtue of this role, it can regulate cellular levels of NAD and so impact not only cellular energetics but also NAD-dependent enzymes such as sirtuins. Although it lacks a signal peptide, PBEF is released by a variety of cells, and elevated levels can be found in the systemic circulation of patients with a variety of inflammatory diseases. As an extracellular cytokine, PBEF can induce the cellular expression of inflammatory cytokines such as TNF-{alpha}, IL-1β, and IL-6. Finally, PBEF has been shown to be an adipokine expressed by fat cells that exerts a number of insulin mimetic and antagonistic effects. PBEF expression is up-regulated in a variety of acute and chronic inflammatory diseases including sepsis, acute lung injury, rheumatoid arthritis, inflammatory bowel disease, and myocardial infarction and plays a key role in the persistence of inflammation through its capacity to inhibit neutrophil apoptosis. This review summarizes the admittedly incomplete body of emerging knowledge about a remarkable new mediator of innate immunity.

Key Words: inflammation • NAD • insulin • cytokine • sepsis • metabolic syndrome


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INTRODUCTION
 
Innate immunity in the vertebrate host is affected through the coordinated and dauntingly complex interactions of literally thousands of biochemical mediators. A single bolus i.v. infusion of endotoxin to a healthy human volunteer, for example, results in the differential expression of 3147 genes [1 ] or more than 10% of the human genome.

The families of endogenous inflammatory mediators are diverse, spanning genes involved in transducing signals between immune cells (the ILs) and genes involved in such fundamental processes as programmed cell death, intermediary metabolism, coagulation, inhibition of inflammation, activation of adaptive immunity, and tissue repair. To this exhaustive list of endogenous mediators must be added an intriguing newcomer—pre-B cell colony-enhancing factor (PBEF)/visfatin/nicotinamide phosphoribosyltransferase (Nampt)—a pleiotropic protein that is highly conserved in evolution and unique in its structural and functional profile.

Human PBEF was first identified by Samal and colleagues in 1994 [2 ] as a protein that was secreted by activated lymphocytes in bone marrow stromal cells and that synergized with IL-7 and stem cell factor (SCF) to stimulate early stage B cell formation. Maximal levels of mRNA transcripts are found in peripheral blood leukocytes, liver, and lung; however, the protein is ubiquitously expressed in all tissues [3 ]. It is also highly conserved, with orthologs in bacteria [4 ], invertebrate sponges [5 ], Drosophila, amphibians (Xenopus), fish [6 ], birds (chicken), and mammals [7 ].

Samal et al. [2 ] reported that although PBEF lacks a characteristic signal peptide necessary for extracellular secretion of mature protein, the 3' untranslated region (UTR) contains multiple TATT motifs—a characteristic of cytokines—and that it is present in conditioned medium from activated lymphocytes and COS cells [2 ]. Further evidence that PBEF was a cytokine came from studies showing that PBEF is up-regulated in distended or infected human fetal membranes and secreted by cultured amniotic epithelial cells [8 , 9 ] and that PBEF is up-regulated in activated neutrophils and that recombinant PBEF inhibits neutrophil apoptosis when added to the culture medium [10 ].

However, other work suggested that the predominant activity of PBEF is intracellular. A bacterial gene, NadV, having substantial homology to PBEF, was shown to be a nicotinamide adenine dinucleotide (NAD) phosphoribosyl transferase and to enable the bacterium, Haemophilus ducreyi, to grow in the absence of exogenous NAD [4 ]. Rongvaux and colleagues [11 ] confirmed that murine PBEF activity has a Nampt and that it catalyzes the rate-limiting step in NAD biosynthesis, the conversion of nicotinamide to nicotinamide mononucleotide (NMN). Moreover, the murine gene was able to confer NAD independence when cloned into Actinobacillus pleuropneumoniae, a bacterium lacking the NadV gene, thus confirming an enzymatic activity that is evolutionarily conserved from bacteria to mammals [11 ]. Kitani and colleagues [3 ] cloned rat PBEF and reported that its cellular distribution varies with the growth phase of the cell, being predominantly nuclear in nonproliferating cells and predominantly cytoplasmic in proliferating cells, leading them to postulate a role for PBEF in cell cycle regulation. Our studies [10 ] have shown that although PBEF is released from cells, it exerts an antiapoptotic activity in neutrophils that is dependent on the presence of intracellular PBEF, as it can only be replicated by extracellular PBEF when the translation of intracellular PBEF is intact.

A third role for PBEF was identified by Fukuhara and colleagues [12 ], who identified a novel adipokine—a protein mediator secreted by fat cells—that they designated visfatin, because of its high levels of expression in visceral fat cells. Visfatin was shown to activate its target cells by binding to the insulin receptor (IR), although at a site distinct from insulin, and to exert a variety of insulin-mimetic effects, including enhancing glucose uptake and increasing triglyceride synthesis.

Three apparently distinct biologic activities have given rise to three names for this unique protein. It is structurally unique and biologically indispensable: Deletion of the PBEF gene results in death early during murine embryogenesis [12 ]. Emerging data implicate PBEF/Nampt/visfatin in the pathogenesis of a number of different human diseases that share an inflammatory basis—chronic diseases such as rheumatoid arthritis [13 ] and Type 2 diabetes [14 ] and acute, life-threatening processes such as acute lung injury (ALI) [15 ] and sepsis [10 ]. Moreover, PBEF has also been implicated in tumorigenesis [16 , 17 ].

This review summarizes findings from just over a decade of work following discovery of PBEF, focusing in particular on its interconnected roles in innate immunity, inflammation, and energy metabolism.


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GENE AND PROTEIN STRUCTURE
 
PBEF lacks sequence homology with any other known protein at the gene or protein level; however, its structure is similar to that of a nicotinic acid phosphoribosyl transferase (NAPRTase) from Thermoplasma acidophilum [18 ], and features of the amino acid sequence are shared with Nampt genes from primitive metazoans (marine sponges) and prokaryotic organisms that are conserved through evolution [11 ] (Fig. 1 ).


Figure 1
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  		Figure 1. Sequence alignment of the predicted murine PBEF amino acid sequence with homologues found in other species. Black, shaded regions (with white text) indicate residues that are more than 80% conserved in all species; gray, shaded regions indicate residues that are more than 60% conserved in all species. Sequence IDs/percent identity compared with human are as follows: human AAA17884; mouse AAH04059/95%; carp BAA96290/85%; sponge (Suberites domuncula) CAB65409/58%; H. ducreyi AAP96260/30%. Sequences were obtained from the Entrez Protein database at the National Center for Biotechnology Information (NCBI) website (http://www.ncbi.nlm.nih.gov/) and were aligned using the ClustalW server at the European Bioinformatics Institute (http://www.ebi.ac.uk/). The sequence alignment was edited with the Jalview Java Alignment Editor [19 ].

The gene for PBEF spans a length of 34.7 kb on the long arm of chromosome 7 (7q22) [8 ]. It incorporates 11 exons and 10 introns, the first exon including the 5' UTR and a signal peptide and the final exon encoding the carboxy terminus and the 3' UTR [8 ]. The cDNA comprises 2.367 kb and a single open-reading frame and encodes a peptide product of 52 kDa [2 ]. Three separate mRNA species of 2.0, 2.4, and 4.0 kb are recognized, likely reflecting alternate splicing of exons or the use of alternate polyadenylation sites; the dominant transcript is the 2.4-kb species [2 ].

Analysis of the 3.2-kb sequence upstream of the transcription initiation site (ATG codon) of the PBEF gene revealed the presence of two distinct promoters in the 5'-flanking region, suggesting that the gene may be differentially expressed in different tissues [8 ] (Fig. 2 ). The proximal 1.4-kb is GC-rich and contains 12 SP-1-binding sites as well as numerous AP-2- and LF-1-binding sites, and the distal promoter region has several CAAT boxes and TATA-like sequences and binding sites for CCAAT/NF1, NF-{kappa}B, NF-IL-6, the GR, and AP-1. The binding sites for NF-1 and AP-2 are mainly in the proximal promoter region, whereas AP-1 sites are uniformly distributed. Both promoter regions contain hormonally and chemically responsive regulatory elements, which include the binding sites for the GR, corticotropic-releasing factor, CREB, and NFs such as NF-IL-6. A NF-{kappa}B-binding site is only present in the distal promoter region, although a second NF-{kappa}B consensus sequence is present in the third intron. The pattern has been interpreted as suggesting that the proximal promoter is more susceptible to regulation by phosphorylation and by hormones [8 ]. Subsequent studies identified other transcription factor binding sites—two STAT-binding sites in the proximal and distal promoter regions [13 ] and two functional HREs in the proximal promoter region [17 ].


Figure 2
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  		Figure 2. Schematic representation of regulatory elements in the 5'-upstream region. The line marked nt (nucleotides) shows the distance from the transcription initiation site, which is marked at +1. The translation initiation codon (ATG) is marked with an arrow. Exons 1 and 4 are represented by black blocks. The 5'-upstream region can be divided into two segments: the proximal (–1400 to +1) is more GC-rich, and the distal (–3200 to –1400) has more AT bases. Symbols used to represent regulatory elements are shown above the diagram. The box with blue diamonds represents one of the TATA boxes. Boxes with red stripes were putative hypoxia-inducible factor (HIF)-responsible elements (HREs), as described by Bae et al. [17 ]. Two single nucleotide polymorphisms (SNPs) in the PBEF promoter (T-1001G and C-1543T), described by Garcia and Moreno Vinasco [20 ], are also shown. This figure was modified and reproduced with permission from ref. [8 ]. SP1, Specificity protein 1; CRE, cAMP-response element; GR, glucocorticoid receptor; LF-1, lymphoid enhancer-binding factor; HNF-5, hepatocyte nuclear factor-5.

Transcription factors such as NF-1, AP-1, AP-2, NF-{kappa}B, and STAT regulate cytokine expression [21 , 22 ], and their presence in the promoter region suggests a role for PBEF in innate and adaptive immunity. NF-{kappa}B is activated in response to mechanical stimuli [23 , 24 ]; therefore, the presence of a NF-{kappa}B consensus sequence might explain the up-regulation of PBEF expression by mechanical distention in fetal membranes [8 ] or lung endothelium during mechanical ventilation [20 ]. Similarly, STAT-3 is the principle transcription factor activated by IL-6, and its presence in the PBEF promoter might account for the induction of PBEF expression by IL-6 in human synovial fibroblasts [13 ].

Like many other genes involved in the innate immune response, the gene for PBEF is polymorphic [25 ]. Ye and colleagues [15 ] identified two SNPs in the promoter region of the gene: T-1001G and C-1543T, the former in the proximal promoter region and the latter in the distal. Transcription of PBEF was reduced in patients with the T variant of the C-1543T SNP, and subsequent work has suggested that the C-1543T SNP is associated with a reduced risk of acute respiratory distress syndrome (ARDS), whereas the T-1001G SNP confers an increased risk of ARDS and of Intensive Care Unit (ICU) mortality [26 ]. A C-948A SNP has been associated with a modestly increased risk of Type 2 diabetes and elevated levels of acute-phase proteins [27 ] and a C-948G SNP with an increased diastolic blood pressure in obese children [28 ].

Two observations regarding the genomic structure of PBEF raise questions about its role as a secreted cytokine. First, the 5'-flanking region of the PBEF gene lacks the classical sequence motif (GPuGPuTTPyCAPy) that is commonly seen in other hematopoietic cytokines [8 ]. Second, analysis of mRNA transcripts failed to reveal cytokine-specific secretion sequences, such as the consensus leader sequence or a canonical caspase-1 cleavage site [2 ]. Studies about its release from 3T3-L1 adipocytes suggest a mechanism of transport that does not conform to conventional secretory pathways [29 ].

Wang et al. [18 ] and Kim et al. [30 ] have recently resolved the crystal structures of mouse and rat PBEF (Fig. 3 ). Both groups reported that functional PBEF forms a homodimer composed of two identical subunits, both of which contribute to the active site that catalyzes the conversion of nicotinamide and phosphoribosyl-pyrophosphate to form NMN [30 ]. Although PBEF has no substantial sequence identity to other phosphoribosyltransferase enzymes, its tertiary structure is similar to that of the dimeric NAPRTase from T. acidophilum, and so, it may be considered as a Type 2 phosphoribosyltransferase [18 ]. Comparison of the sequence of the rat PBEF dimer active site with that of 13 different organism reveals a high degree of conservation of the sequence of amino acid residues responsible for the nicotinamide ring (substrate) and NMN (product)-binding abilities [30 ]. In addition, the PBEF dimer can hydrolyze ATP and undergo autophosphorylation, enhancing its Nampt activity [18 ].


Figure 3
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  		Figure 3. Crystal structure of PBEF. Schematic ribbon diagram of the PBEF dimer comprising two monomers, 491 residues in length. B-strands are represented by orange arrows, and a-helices are represented by green cylinders. Structures were obtained from the molecular modeling database at NCBI (http://www.ncbi.nlm.nih.gov/Entrez/structure.html) [31 ]. Structures were viewed and highlighted with a Cn3D viewer, Version 4.1, downloaded from ref. [32 ].


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PBEF AS Nampt: THE NAD CONNECTION
 
NAD is an essential cofactor in a number of fundamental intracellular processes by virtue of its ability to transfer electrons during redox reactions, to modulate the activity of key regulators of cellular longevity, and to serve as a substrate for the generation of other biologically important molecules [33 ]. NAD synthesis in mammals occurs by one of two principle pathways [34 ] (Fig. 4 ). The de novo synthetic pathway converts the amino acid tryptophan to quinolinic acid, which in turn, is converted to NaMN, then converted to deamido-NAD through the action of nicotinamide/Nmnat, and finally, to NAD, catalyzed by NAD synthetase.


Figure 4
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  		Figure 4. NAD biosynthesis in vertebrates. NAD can be synthesized from the de novo pathway or from one of the three salvage pathways. De novo synthesis begins with tryptophan, which undergoes several reactions to form quinolinic acid (reactions not shown), which is converted to nicotinic acid mononucleotide (NaMN) by quinolate phosphoribosyltransferase (Qprt). NaMN is then adenylylated by NaMN adenylyltransferase (Nmnat) to form nicotinate adenine dinucleotide (NaAD), which is converted to NAD by glutamine-dependent NAD synthetase. The three salvage pathways are 1) nicotinic acid pathway, nicotinic acid salvaged by NAPRTase (Npt) to form NaMN; 2) nicotinamide pathway, nicotinamide is salvaged by Nampt/PBEF to NMN, which is adenylylated to form NAD by Nmnat; 3) nicotinamide ribose pathway, nicotinamide ribose is salvaged by nicotinamide riboside kinases (Nrk) to form NMN.

The quantitatively more important mechanism of NAD synthesis in mammalian cells occurs through the so-called salvage pathway. Nicotinamide, resulting from intracellular degradation of NAD, is converted to NMN by Nampt and NMN to NAD by Nmnat [35 ]. Nampt activity was first described more than 40 years ago [36 , 37 ]. However, it was not until 2002 that the responsible enzyme was demonstrated to be identical to PBEF and found to be the rate-limiting enzyme in NAD biosynthesis [11 ]. It has been demonstrated recently that NAD can also be synthesized from niacin (nicotinic acid, vitamin B3) in human cells through the activity of a novel NAPRTase [38 ]. NAD synthesis appears to be localized to specific and distinct subcellular compartments—the nucleus, the Golgi, and the mitochondria; within each of these separate compartments, distinct isoforms of the enzyme Nmnat are involved in the synthetic process [39 ]. NAD turnover within the cell is a dynamic process. The normal intracellular concentration is ~500 µM, and the half-life of the NAD molecule, only 1–2 h [40 ]. NAD can modulate the expression of innate immunity in a number of ways.

NAD is an essential cofactor in cellular respiration and the generation of a respiratory burst. NAD is phosphorylated by NAD kinase to generate NADP [41 ]. The transfer of an electron from NADP to molecular oxygen, through the activity of the multicomponent NADPH oxidase, initiates the respiratory burst and the generation of a family of reactive oxygen species that plays a crucial role in antimicrobial defenses and in the regulation of intracellular signaling [42 43 44 ].


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Sirtuins (SIRTs) and epigenetic regulation of inflammatory gene expression
 
Beyond its central role in oxidative metabolism, NAD is increasingly recognized to be involved in the regulation of intracellular signaling (Fig. 5 ). NAD is an essential cofactor for the activity of a family of Class 3, NAD-dependent HDACs known as SIRTs [46 ], which are mammalian orthologs of a highly conserved gene known as silent information regulator 2 (Sir2), first identified in yeast and subsequently, in species from bacteria to humans, as contributing to prolongation of lifespan in response to caloric restriction [47 , 48 ]. The SIRT family in mammals comprises seven members, SIRT1–7, which differ with respect to their subcellular localization; SIRT1 is primarily a nuclear protein, SIRT2 a cytoplasmic protein, and SIRT3, five mitochondrial proteins [46 ].


Figure 5
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  		Figure 5. NAD-consuming enzymes. NAD can be consumed as a substrate for ADP-ribose transfer, cyclic ADP (cADP)-ribose synthesis, and protein lysine deacetylation, producing nicotinamide as the end-product. ADP-ribose transferases (ARTs) and poly(ADP-ribose) polymerases (PARPs) transfer ADP-ribose from NAD to another protein or to another ADP-ribose, forming poly(ADP-ribose). cADP-ribose synthases, also known as lymphocyte antigens CD38 and CD157, produce the Ca2+-mobilizing second messenger cADP-ribose from NAD. These enzymes also hydrolyze cADP-ribose to ADP-ribose. SIRTs are Type 3 histone deacetylases (HDACs) or more precisely, Type 3 protein lysine deacetylases. It binds to NAD and a protein that contains an acetylated lysine. It catalyzes the formation of acetylated ADP-ribose by deacetylation of the lysine residue. The acetylated ADP-ribose then rearranges to form a mixture of 2'- and 3'-O-acetyl-ADP-ribose (OAADPr). This figure was modified from ref. [45 ].

Sir2 and its human orthologs consume NAD+ and generate nicotinamide as they hydrolytically remove an acetyl group from a lysine residue of their target proteins [49 ]. The deacetylation process is linked to the hydrolysis of NAD+, yielding nicotinamide and an intermediate—OAADPr [50 ]. Sir2 enzymes are inhibited by free nicotinamide that can bind noncompetitively to the NAD+ binding site of the molecule [51 ]. SIRT1 is capable of trafficking from the cytoplasm to the nucleus and back, suggesting that subcellular localization represents an important mechanism of regulation of SIRT1 activity [52 ].

SIRT activity has been implicated in a broad range of cellular processes including gene expression, cell cycle regulation, apoptosis, metabolism, and aging [46 ]. SIRT family members deacetylate lysine residues in target proteins; the consequences are wide-ranging. Deacetylation of the RelA/p65 subunit of NF-{kappa}B at lysine 310 inhibits the binding of NF-{kappa}B to its consensus sequence in a large number of genes involved in innate immunity and so inhibits their expression [53 54 55 ]. SIRT1 can physically interact with the transcription factor FoxO1, a negative regulator of insulin/insulin growth factor-1 signaling, via a conserved LXXLL motif that enables it to deacetylate and therefore, inhibit FoxO1-mediated gene regulation, decreasing blood glucose levels and activating gluconeogenesis [56 , 57 ]. SIRT1 can also regulate the activity of other transcription factors, including peroxisone proliferator-activated receptor {gamma} (PPAR{gamma}), PPAR{gamma}-coactivator 1{alpha}, and p300/CREB-binding protein [58 , 59 ].

It has been suggested that the Nampt activity of PBEF might regulate SIRT-dependent activities by virtue of its capacity to provide the SIRT cofactor, NAD [60 ]. Using microarray analysis, van der Veer and colleagues [61 ] found that PBEF was up-regulated during the maturation of vascular smooth muscle cells (SMCs), a state characterized by an elongated morphology, decreased apoptosis, increased expression of contractile proteins, and the ability to contract in response to vasoactive agonists. PBEF knockdown prevented maturation and resulted in increased apoptosis, whereas overexpression of PBEF in a smooth muscle cell line reproduced features of maturation. Overexpression of PBEF further increased intracellular levels of NAD and increased HDAC activity [61 ]. In subsequent work, this same group provided evidence that PBEF can extend the lifespan of human SMCs by activating SIRT1 and inhibiting accumulation of p53 [62 ]. PBEF expression and Nampt activity declined as cells replicated, and PBEF overexpression increased the number of replicative cycles a cell could undergo before senescence. PBEF increased the expression and activity of SIRT1, and the transfection of cells with dominant-negative SIRT1 blocked the effects of PBEF in delaying senescence. Finally, overexpression of PBEF reduced the measured amount of p53 and accelerated its degradation, suggesting that PBEF delays cellular senescence through SIRT1-mediated deacetylation and inactivation of p53 [62 ].


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ADP ribosylation
 
NAD also serves as the substrate for a variety of ADP ribosylation reactions—phylogenetically ancient reactions that occur in species from archaebacteria to mammals and that play fundamental roles in the regulation of DNA repair, cell cycle regulation, intracellular signaling, and apoptosis [40 ] (Fig. 5) . ADP-ribosylation reactions involve the covalent attachment of molecules of ADP-ribose to target proteins or to each other to create polymers of ADP-ribose. Four broad classes of such reactions are recognized: mono-ADP-ribosylation; poly-ADP-ribosylation; ADP-ribose cyclization; generation of OAADPr [40 ].

Mono-ADP-ribosylation is catalyzed by enzymes that ADP-ribosylate specific amino acid residues in their protein targets, altering their functional properties [63 ]. Mono-ADP ribosylation has been implicated as the mechanism of certain bacterial toxins, including pertussis toxin, cholera toxin, and some clostridial toxins. Its role in the regulation of innate immunity is less clear. Mono-ADP-ribosylation of neutrophil defensins, a process that can be detected in bronchoalveolar lavage fluid (BALF) from smokers but not from nonsmokers, results in reduced defensin antimicrobial activity [64 ]. SIRTs may also express activity such as mono-ADP-ribosyltransferases [65 ], and nuclear proteins such as high-mobility group box 1 [66 , 67 ] can be modified by mono-ADP-ribosylation [68 ].

PARP-1 is the prototype of a family of 18 enzymes that catalyze the polymerization of ADP-ribose into long, branching chains and the covalent attachment of ADP-ribose to glutamic acid or aspartic acid residues [69 ]. Like other proteins involved in NAD metabolism, PARP-1 is highly phylogenetically conserved. It is very abundant in the nucleus, with one molecule per thousand DNA base pairs [70 ]. PARP activity is rapidly increased in response to DNA strand breaks, resulting in depletion of intracellular NAD and reduction in SIRT1 activity [71 , 72 ]. When DNA damage is minimal, reparative mechanisms are invoked; however, in the face of more extensive DNA damage, PARP activation can result in apoptotic or necrotic cell death [73 ]. Repletion of intracellular NAD by addition of NAD to culture media can prevent PARP-induced cell death in vitro [74 ]; whether endogenous Nampt activity can similarly regulate PARP activation is unknown.

NAD can be converted to cADP-ribose through the activity of CD38, a plasma membrane-associated glycoprotein. Studies in CD38 knockout mice reveal levels of NAD that are 20 times higher than those of wild-type mice [75 , 76 ] and show that deletion of CD38 results in impaired neutrophil chemotaxis and increased susceptibility to bacterial infection [77 ]. cADP-ribose serves as a second messenger, regulating the release of calcium from intracellular stores. CD38 can also increase the influx of extracellular calcium by potentiating the activation of the nonselective cation channel, transient receptor potential melastatin 2 [78 ].


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NAD as an extracellular mediator
 
NAD can be detected at nanomolar levels in human serum, and there is increasing evidence that extracellular NAD can modulate the function of cells of the innate immune system [79 ]. Although the presence of NAD in the extracellular environment may be a consequence of leakage of intracellular NAD during cell death, connexin 43 channels have been shown to mediate the passage of NAD to the external environment of intact, viable cells [80 ]. Extracellular NAD appears to interact with cells through CD38 or a family of ARTs (ART1–4) that are GPI-linked receptors [79 ]. For example, ART2 catalyzes ADP ribosylation and activates the purinoreceptor P2X7, resulting in calcium influx and apoptosis in T cells [81 ]. NAD+ can also activate neutrophils to increased calcium influx and increased production of reactive oxygen intermediates through interactions with the P2Y11 purinergic receptor [82 , 83 ]. Exogenous NAD can block NF-{kappa}B activation and increased permeability in confluent monolayers of gut epithelial cells cultured with LPS [84 ] and increase oxygen use by gut epithelial cells stimulated with a mixture of proinflammatory cytokines [85 ].


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PBEF: A PROINFLAMMATORY CYTOKINE
 
PBEF was originally described as a cytokine-like molecule that synergized with IL-7 and SCF to promote pre-B cell colony formation in vitro [2 ]. Consistent with the hypothesis that PBEF is a cytokine-like molecule, PBEF expression in lymphocytes could be induced by lectin and superinduced by cycloheximide, and PBEF protein could be found in the culture medium of activated lymphocytes [2 ]. Engagement of the TNF superfamily member TALL-1 in B lymphocytes or B cell lymphoma cells induces expression of PBEF [86 ], and pre-B cells themselves also express PBEF following stimulation by IFN-{gamma} [87 ].

Subsequent work has shown PBEF to be widely induced by inflammatory stimuli in cells involved in innate immunity, specifically neutrophils, monocytes, and macrophages, as well as in epithelial and endothelial cells (Table 1 ). Studies by Ognjanovic et al. [8 , 9 ] examined the proinflammatory properties of PBEF on human fetal membranes. PBEF was expressed in human amniotic epithelial cells stressed by acute distension, a process that occurs in late gestation as the uterus is rapidly growing; expression of PBEF was higher in the pre-term membrane than in the term membrane [91 ]. Moreover, PBEF expression was significantly increased in severely infected fetal membranes compared with normal tissue [8 ]. PBEF expression in human amniotic epithelial cells could be induced by inflammatory stimuli in vitro—exogenous stimuli such as LPS and endogenous inflammatory stimuli such as TNF-{alpha}, IL-1β, and IL-6 [8 ]. The ability of IL-6 to induce PBEF expression was further investigated by Nowell et al. [13 ], who reported that PBEF is significantly up-regulated by IL-6 in human synovial fibroblast cell lines by a STAT-3-dependent pathway. Consistent with this finding, mice with a genetic deletion of IL-6 failed to show an increase in PBEF expression in experimental arthritis.


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  		Table 1. Inflammatory Mediator-Induced Expression of PBEF/Visfatin

In contrast, Kralisch and colleagues reported that IL-6 inhibits PBEF transcription [92 ] and that dexamethasone induces, whereas TNF-{alpha}, growth hormone, and β-adrenergic agents suppress, PBEF transcription in 3T3-L1 adipocytes [93 ]. These findings were confirmed by MacLaren and co-workers [94 ], who reported that susceptibility of PBEF transcription to hormonal stimulation changes as 3T3-L1 preadipocytes mature to adipocytes. On the other hand, TNF-{alpha} has been reported to increase PBEF expression in cultured human visceral fat cells [95 ].

PBEF can also stimulate the release of cytokines involved in normal and infection-induced parturition [96 , 97 ]. Ognjanovic and Bryant-Greenwood [9 ] showed that recombinant PBEF increases IL-6 and IL-8 expression in amniotic epithelial cells. As PBEF expression is induced by mechanical and inflammatory stimuli, these authors suggested that PBEF plays a role in the cytokine network that facilitates normal, spontaneous labor and that initiates infection-induced pre-term labor. PBEF has also been shown to induce the transcription and translation of IL-1β, IL-1ra, IL-6, IL-10, and TNF-{alpha} in PBMCs and of IL-1β, IL-6, and TNF-{alpha} in CD14+ monocytes [98 ]. Moreover, it increases cell surface expression of costimulatory molecules, such as CD54, CD40, and CD80. Using inhibitors of specific signal transduction cascades, these investigators implicated the PI-3K and MAPK (p38, MEK1, and JNK) pathways in PBEF-mediated signaling [98 ].


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PBEF AS VISFATIN: THE INSULIN CONNECTION
 
Fukuhara and co-workers [12 ] reported that PBEF is also an adipokine produced by visceral fat that can engage and activate the IR. This publication was recently retracted because of questions regarding the reproducibility of the PBEF/IR interaction across varying lots of recombinant protein [99 ]; nonetheless, it stimulated a number of reports, indicating a novel extracellular role for PBEF in a spectrum of metabolic disorders.

Adipokines (also known as adipocytokines) are members of a family of secreted proteins released by fat cells that regulate a variety of physiological and pathological processes, including immunity and inflammation [100 , 101 ], and whose activity has been implicated in the pathogenesis of the metabolic syndrome—a cluster of disorders including diabetes mellitus, hyperlipidemia, hypertension, and increased risk of cardiovascular disease [102 , 103 ].

By comparing differential gene expression between visceral and s.c. fat from two female volunteers, Fukuhara et al. [12 ] identified a novel adipokine that was preferentially expressed in visceral fat and that they designated as visfatin; analysis of the amino acid sequence of visfatin revealed it to be identical with PBEF. Recombinant visfatin was shown to lower blood glucose levels, independent of any activity on insulin levels, and to exert a variety of activities ascribed to insulin.


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Intracellular signaling through the IR
 
Insulin is the central hormone-regulating glucose homeostasis. The mechanisms by which it engages its receptor and activates intracellular signaling and the alterations in these events that result in insulin resistance have been well-studied [104 105 106 ]. Normal insulin signaling is initiated through the binding of insulin to the {alpha}-subunit of the IR, resulting in a conformational change in the receptor and inducing autophosphorylation on tyrosine residues of the transmembrane β-subunit. This autophosphorylation induces an additional conformational change that activates the protein tyrosine kinase activity of IR [107 ]. The activated IR can then transduce intracellular signals via a number of intracellular substrates.

The most common substrates of IR are the IR substrate proteins that serve as docking proteins for second messengers such as PI-3K. Activated PI-3K leads to generation of phosphatidylinositol phospholipids, which in turn activate phophatidylinositol phosphate-dependent kinase-1 and Akt/protein kinase B, resulting in translocation of glucose transporters from cytoplasmic vesicles to the cell surface for increased glucose transport [108 ]. Also downstream of the IR are isoforms of Src homology collagen proteins, which are phosphorylated by the tyrosine kinase activity of IR and trigger activation of members of the MAPK family, promoting cell growth and protein synthesis [109 , 110 ].


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PBEF/visfatin and insulin: analogs or antagonists?
 
Studies in diabetic patients and healthy controls suggest that circulating PBEF levels may be regulated by glucose. Haider et al. [111 ], for example, found that increasing the concentration of glucose administered to healthy humans resulted in increased plasma concentrations of PBEF and that the rise in PBEF levels could be prevented by coinfusion of insulin or somatostatin. Furthermore, s.c. and visceral adipocytes released PBEF upon stimulation with glucose. A number of authors have reported elevated PBEF levels in patients with Type 1 or 2 or gestational diabetes [14 , 112 113 114 115 116 ], although others have suggested that levels may be normal [117 ] or even decreased [118 ] in diabetic patients. In addition, Berndt and colleagues [119 ] could find no correlation between levels of PBEF and those of insulin or glucose in a cohort of obese patients, and no evidence that PBEF levels responded to glucose infusion. Variability in the assays used to detect PBEF/visfatin may account for this discrepancy [120 ].

Whether PBEF binds to the IR remains controversial [99 ]. PBEF exerts an insulin-like activity as a growth factor for osteoblasts [121 ]. Moreover, others have reported that like insulin, PBEF induces tyrosine phosphorylation of IR and increases glucose transport into osteoblasts, stimulating osteoblast proliferation and increasing Type 1 collagen expression, and that these effects can be ablated with an IR inhibitor, hydroxy-2-naphthalenylmethyl phosphonic acid [121 ].

It has, however, been suggested that the extracellular effects of PBEF might not be a consequence of a classic receptor-ligand interaction but rather, reflect an extracellular Nampt activity [60 ]. Consistent with this hypothesis, recent work has shown that extracellular PBEF exerts Nampt activity and that haplodeficiency or specific inhibition of Nampt impairs NAD biosynthesis and insulin secretion by pancreatic islet cells [122 ].


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PBEF/VISFATIN IN CLINICAL INFLAMMATION
 
Accumulating data associate increased PBEF expression with a variety of acute and chronic inflammatory conditions. In addition to its roles in amnionitis [9 ] and metabolic syndrome [112 , 115 ] described above, increased PBEF expression has been implicated in life-threatening disorders of the critically ill, in the pathogenesis of atherosclerosis, and in a number of rheumatic diseases.


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PBEF in sepsis and ALI
 
Sepsis, a life-threatening disorder that results from a dysregulated innate immune response to infection, is a common cause of global morbidity and mortality, responsible for more than 200,000 deaths per year in North America [123 , 124 ]; its rates appear to be on the increase [125 ]. Increased circulating levels of cytokines with pro- and anti-inflammatory activity are evident in patients with sepsis and correlate with an increased risk of mortality [126 ]. Multiple abnormalities in innate and adaptive immunity are evident in patients with sepsis [127 ]. Prominent among these is neutrophilia, with evidence of disseminated systemic neutrophil activation, and many lines of evidence link activated neutrophils to the organ injury of sepsis [128 , 129 ].

Neutrophils are constitutively apoptotic cells, which in a quiescent state, survive only 6–8 h in vivo before dying an apoptotic death [130 ]. However, neutrophils harvested from the circulation of septic patients show marked inhibition of the apoptotic process in association with evidence of enhanced respiratory burst capacity [131 , 132 ]. PBEF plays a requisite role in this inhibition [10 ]. Transcription of the PBEF gene is increased in neutrophils from septic patients; prevention of PBEF translation through the use of an antisense oligonucleotide largely restores the normal kinetics of apoptosis. Moreover, the incubation of quiescent neutrophils from healthy volunteers with recombinant PBEF results in dose-dependent inhibition of apoptosis, and antisense PBEF prevents the inhibition of apoptosis that results from exposure to LPS or to a variety of host-derived inflammatory cytokines [10 ]. The mechanism of PBEF-mediated inhibition of apoptosis is unclear. Transcription of PBEF in response to LPS is delayed, reaching maximal levels 10 h after exposure. An antiapoptotic effect of extracellular PBEF is suggested, not only by the fact that exogenous PBEF inhibits apoptosis but also by the observation that conditioned medium from LPS-treated neutrophils contains an antiapoptotic activity and that this activity is abolished if cells are treated with PBEF antisense oligonucleotides. On the other hand, exogenous PBEF alone is not sufficient to inhibit apoptosis, as recombinant PBEF fails to delay apoptosis when the translation of endogenous PBEF is blocked.

Ye and colleagues [15 ] have implicated PBEF in the pathogenesis of ALI, a common, acute inflammatory process affecting the lung in critically ill patients in an ICU. They reported that PBEF transcription is significantly increased in lung tissue from critically ill patients with ALI and in a canine model of lung injury and that PBEF protein levels were increased significantly in BALF and serum from patients with ALI. Immunohistochemical staining of canine-injured lung tissues localized PBEF expression to vascular endothelial cells, infiltrating neutrophils and Type 2 alveolar epithelial cells, and in vitro studies confirmed that microvascular endothelial cells expressed PBEF in response to LPS, TNF-{alpha}, IL-1β, and mechanical stretch [15 ]. In vitro studies show that expression of PBEF in pulmonary artery endothelial cells increases thrombin-mediated vascular permeability [88 ], suggesting that enhanced PBEF expression may mediate the early increase in vascular permeability that is characteristic of ALI.


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PBEF in atherosclerosis
 
Inflammation has also been implicated in such common vascular diseases as acute myocardial infarction and thrombotic stroke [133 ]. A cytokine-like activity of PBEF has been implicated in the pathogenesis of unstable atherosclerosis. Dahl and colleagues [89 ] showed that PBEF expression is up-regulated in plaque from the carotid artery of patients with symptoms of stroke and at the sites of plaque rupture in patients with acute myocardial infarction. They further found that PBEF expression could be induced in monocytic THP-1 cells by TNF-{alpha} and oxidized LDL and that recombinant PBEF induced monocyte matrix metalloproteinase-9 activity, suggesting that PBEF plays an important role in atherogenesis and plaque destabilization.


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PBEF in chronic inflammatory disorders
 
Increased PBEF expression has also been identified in a variety of chronic inflammatory diseases, including rheumatoid arthritis [13 , 134 ], inflammatory bowel disease [98 ], and psoriasis [135 ]. Obesity, as a feature of the metabolic syndrome, can be considered an inflammatory disorder [136 ]. There are conflicting reports about the relationship of obesity to circulating levels of PBEF/visfatin; some authors report an increased level of PBEF in obese subjects [137 138 139 ] and others finding no apparent relationship [140 ] or even a negative correlation [141 ]. Similarly, weight loss has been reported to increase [142 ] and reduce [143 ] circulating levels of PBEF.

Finally, HIF-1 induces PBEF expression in breast cancer cells through interactions with two HIF response elements in the PBEF promoter region, suggesting that PBEF expression is induced in response to hypoxia in the cellular microenvironment.


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CONCLUSIONS
 
Of the many host-derived proteins that play an integral role in the expression of innate immunity, PBEF/visfatin is one of the newest and one of the most unusual. Highly conserved throughout evolution, PBEF has a unique structure and no obvious homology to other known proteins. It has fundamentally important roles in two processes critical to cellular energetics: the synthesis of NAD and the uptake of energy substrates mediated by the actions of insulin, one of which occurs through an activity of PBEF as an intracellular enzyme and the other as a secreted cytokine. Further, it translates these activities into a potent influence on the processes of cellular growth and programmed cell death.

The biology of PBEF/visfatin is complex, and many key questions remain unanswered. How, for example, are its distinct intracellular enzymatic activity and extracellular cytokine-like activity reconciled? How is PBEF, a protein lacking a signal peptide or an obvious caspase cleavage site, released from the cell? Is it a secreted product of viable cells or a byproduct of cellular death? How does it interact with the cell: Is its apparent interaction with the IR that of a receptor and a specific ligand, or does it play a more complex role as an adaptor protein modulating insulin signaling? What is its distribution within the cell, and how might its activity be modulated by its intracellular localization? Finally, does the emerging body of evidence about altered levels in a variety of inflammatory disorders identify PBEF as a legitimate target for therapeutic manipulation, or are they simply the lifting of one more veil on a multilayered process whose effective manipulation remains tantalizingly elusive?


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ACKNOWLEDGEMENTS
 
This work was supported in part by a grant from the Canadian Institutes for Health Research, MOP62908.

Received August 28, 2007; revised November 21, 2007; accepted November 27, 2007.


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