Disruption of Poly(ADP-ribose) Polymerase (PARP) Protects Against Stress-Evoked Immunocompromise

Drazen, Deborah L.; Bilu, Donna; Edwards, Nancy A.; Nelson, Randy J.

doi:10.1007/bf03401966

Cited by 17 publications

(14 citation statements)

References 36 publications

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“…PARP-mediated dysfunction of intestinal epithelial cells manifesting in increased permeability has also been demonstrated in monolayers of peroxynitrite-treated CaCo-2BBe cells (Kennedy et al, 1998;Forsythe et al, 2002). Moreover, stress-induced immunosuppression could also be suppressed by genetic ablation of PARP-1, indicating the involvement of PARP-1 in stress-induced immune-cell dysfunction (Drazen et al, 2001).…”

Section: E Parp-1 In Cell Deathmentioning

confidence: 83%

“…PARP seems to play a role in the endothelial dysfunction associated with aging and hypertension (Pacher et al, 2002c,d). Moreover, recent studies implicated PARP activation in the process of dexamethasone-induced (i.e., stress-related) immune suppression (Drazen et al, 2001). Additional PARP-dependent diseases include multiple organ failure of various etiologies, acetaminophen-induced and other forms of toxic liver injury, and sulfur mustard-induced dermal necrosis (Table 4).…”

Section: Q Parp In the Pathogenesis Of Other Diseasesmentioning

confidence: 99%

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The Therapeutic Potential of Poly(ADP-Ribose) Polymerase Inhibitors

Virág

Szabó

2002

Pharmacological Reviews

1,276

1,246

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Poly(ADP-ribose) polymerase-1 (PARP-1) is a member of the PARP enzyme family consisting of PARP-1 and several recently identified novel poly(ADP-ribosylating) enzymes. PARP-1 is an abundant nuclear protein functioning as a DNA nick-sensor enzyme. Upon binding to DNA breaks, activated PARP cleaves NAD(+) into nicotinamide and ADP-ribose and polymerizes the latter onto nuclear acceptor proteins including histones, transcription factors, and PARP itself. Poly(ADP-ribosylation) contributes to DNA repair and to the maintenance of genomic stability. On the other hand, oxidative stress-induced overactivation of PARP consumes NAD(+) and consequently ATP, culminating in cell dysfunction or necrosis. This cellular suicide mechanism has been implicated in the pathomechanism of stroke, myocardial ischemia, diabetes, diabetes-associated cardiovascular dysfunction, shock, traumatic central nervous system injury, arthritis, colitis, allergic encephalomyelitis, and various other forms of inflammation. PARP has also been shown to associate with and regulate the function of several transcription factors. Of special interest is the enhancement by PARP of nuclear factor kappa B-mediated transcription, which plays a central role in the expression of inflammatory cytokines, chemokines, adhesion molecules, and inflammatory mediators. Herein we review the double-edged sword roles of PARP in DNA damage signaling and cell death and summarize the underlying mechanisms of the anti-inflammatory effects of PARP inhibitors. Moreover, we discuss the potential use of PARP inhibitors as anticancer agents, radiosensitizers, and antiviral agents.

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Section: E Parp-1 In Cell Deathmentioning

confidence: 83%

Section: Q Parp In the Pathogenesis Of Other Diseasesmentioning

confidence: 99%

The Therapeutic Potential of Poly(ADP-Ribose) Polymerase Inhibitors

Virág

Szabó

2002

Pharmacological Reviews

1,276

1,246

View full text Add to dashboard Cite

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“…The function of PARP-1 in immunotolerance is less explored to date where the vast bulk of PARP-1 research focus has been on cancer. Recently however, the role of PARP-1 and related family members in immune function are beginning to increase, where steroidal immunosuppression for example may require PARP-1 activity in order to promote T cell apoptosis [279]. Pharmacologic analysis suggests that inhibition of PARP-1 may promote the production of toleragenic dendritic cells, and thus is under consideration in host-versus graft disease and transplantation settings [280].…”

Section: Potential Nad-related Pharmacotherapeutic Strategies For mentioning

confidence: 99%

The Importance of NAD in Multiple Sclerosis

Penberthy¹,

Tsunoda²

2009

CPD

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The etiology of multiple sclerosis (MS) is unknown but it manifests as a chronic inflammatory demyelinating disease in the central nervous system (CNS). During chronic CNS inflammation, nicotinamide adenine dinucleotide (NAD) concentrations are altered by (T helper) Th1-derived cytokines through the coordinated induction of both indoleamine 2,3-dioxygenase (IDO) and the ADP cyclase CD38 in pathogenic microglia and lymphocytes. While IDO activation may keep autoreactive T cells in check, hyper-activation of IDO can leave neuronal CNS cells starving for extracellular sources of NAD. Existing data indicate that glia may serve critical functions as an essential supplier of NAD to neurons during times of stress. Administration of pharmacological doses of non-tryptophan NAD precursors ameliorates pathogenesis in animal models of MS. Animal models of MS involve artificially stimulated autoimmune attack of myelin by experimental autoimmune encephalomyelitis (EAE) or by viral-mediated demyelination using Thieler's murine encephalomyelitis virus (TMEV). The Wld S mouse dramatically resists razor axotomy mediated axonal degeneration. This resistance is due to increased efficiency of NAD biosynthesis that delays stress-induced depletion of axonal NAD and ATP. Although the Wld S genotype protects against EAE pathogenesis, TMEV-mediated pathogenesis is exacerbated. In this review, we contrast the role of NAD in EAE versus TMEV demyelinating pathogenesis to increase our understanding of the pharmacotherapeutic potential of NAD signal transduction pathways. We speculate on the importance of increased SIRT1 activity in both PARP-1 inhibition and the potentially integral role of neuronal CD200 interactions through glial CD200R with induction of IDO in MS pathogenesis. A comprehensive review of immunomodulatory control of NAD biosynthesis and degradation in MS pathogenesis is presented. Distinctive pharmacological approaches designed for NADcomplementation or targeting NAD-centric proteins (SIRT1, SIRT2, PARP-1, GPR109a, and CD38) are outlined towards determining which approach may work best in the context of clinical application.

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“…Systemic inflammatory conditions are associated with the expression of iNOS and with the generation of peroxynitrite, resulting in impaired intracellular energy processes and ultimately multiple organ failure. Mice with targeted disruption of PARP 1 show resistance to acute septic peritonitis,61 hemorrhagic shock,62 endotoxic shock,63 and stress‐evoked immunocompromise 64. Pharmacologic inhibition of PARP improved outcome in a porcine model of severe bacterial sepsis65 and in systemic endotoxemia in rodents 66.…”

Section: Role Of Parp‐1 In Systemic Inflammation and Tissue Injurymentioning

confidence: 99%

Poly(ADP‐Ribose) Polymerase‐1 in Acute Neuronal Death and Inflammation

Skaper

2003

Annals of the New York Academy of Sciences

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Poly(ADP-ribose) polymerase-1 (PARP-1) is an abundant nuclear enzyme that is activated primarily by DNA damage. Upon activation, the enzyme hydrolyzes NAD(+) to nicotinamide and transfers ADP ribose units to a variety of nuclear proteins, including histones and PARP-1 itself. This process is important in facilitating DNA repair. However, excessive activation of PARP-1 can lead to significant decrements in NAD(+), and ATP depletion, and cell death (suicide hypothesis). In response to cellular damage by oxygen radicals or excitotoxicity, a rapid and strong activation of PARP-1 occurs in neurons. Excessive PARP-1 activation is implicated in a variety of insults, including cerebral and cardiac ischemia, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinsonism, traumatic spinal cord injury, and streptozotocin-induced diabetes. The use of PARP inhibitors has, therefore, been proposed as a protective therapy in decreasing excitotoxic neuronal cell death, as well as ischemic and other tissue damage. Excitotoxic brain lesions initially result in the primary destruction of brain parenchyma and subsequently in secondary damage of neighboring neurons hours after the insult. This secondary damage of initially surviving neurons accounts for most of the volume of the infarcted area and the loss of brain function after a stroke. One major component of secondary neuronal damage is the migration of macrophages and microglial cells toward the sites of injury, where they produce large quantities of toxic cytokines and oxygen radicals. Recent evidence indicates that this microglial migration is strongly controlled in living brain tissue by expression of the integrin CD11a, which is regulated in turn by PARP-1, proposing that PARP-1 downregulation may, therefore, be a promising strategy in protecting neurons from this secondary damage, as well. Studies demonstrating an important role for PARP-1 in the regulation of gene transcription have further increased the intricacy of poly(ADP-ribosyl)ation in the control of cell homeostasis and challenge the notion that energy collapse is the sole mechanism by which poly(ADP-ribose) formation contributes to cell death. The hypothesis that PARPs might regulate cell fate as essential modulators of death and survival transcriptional programs is discussed with relation to nuclear factor kappaB and p53.

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Disruption of Poly(ADP-ribose) Polymerase (PARP) Protects Against Stress-Evoked Immunocompromise

Cited by 17 publications

References 36 publications

The Therapeutic Potential of Poly(ADP-Ribose) Polymerase Inhibitors

The Therapeutic Potential of Poly(ADP-Ribose) Polymerase Inhibitors

The Importance of NAD in Multiple Sclerosis

Poly(ADP‐Ribose) Polymerase‐1 in Acute Neuronal Death and Inflammation

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