Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.4.2.30 (PARP)
 13,611 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pertussis toxin (PTX) is known to be mitogenic for T lymphocytes, but its direct action on naive human T cells has not been specified. Herein, we show that PTX induces the proliferation of purified adult CD45RA(+)CD4(+) T cells independently of its ADP-ribosyltransferase activity. PTX directly induces TNF-alpha and IL-2 mRNA expression, modulates the level of several cell surface receptors and induces Forkhead box p3 (Foxp3) protein accumulation in naive CD4(+) T cells. Addition of autologous dendritic cells was found to be required for the production of high levels of IFN-gamma by PTX-stimulated naive T cells. These effects of PTX occurred in conjunction with activation of NF-kappaB and NFAT transcription factors. Overall, responses of neonatal CD4(+) T cells to PTX were similar to those of adult CD45RA(+)CD4(+) naive T cells except for their blunted CD40 ligand up-regulation. We suggest that the adjuvant properties of PTX during primary cell-mediated immune responses involve a direct action on naive T lymphocytes in addition to activation of antigen-presenting cells.
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PMID:Pertussis toxin activates adult and neonatal naive human CD4+ T lymphocytes. 1678 47

Nicotinamide adenosine dinucleotide (NAD) can act as a modulator of multiple immune and inflammatory responses when released into extracellular compartments. These actions of extracellular NAD are largely mediated by a family of mammalian ecto-ADP-ribosyltransferases (ARTs) that covalently modify target extracellular or cell surface proteins by transferring ADP-ribose to arginine or cysteine residues. In this study, we report that bone marrow-derived macrophages (BMDM) from BALB/c mice lack constitutive expression of any of the six murine ecto-ART subtypes, but selectively up-regulate ART2.1 in response to multiple proinflammatory mediators including agonists for TLR and type I and type II IFN. Stimulation of BMDM with LPS, IFN-beta, or IFN-gamma induced high expression of ART2.1, but not ART2.2, as a GPI-anchored cell surface ectoenzyme. ART2.1 expression in response to LPS was potentiated by inhibition of ERK1/2 signaling, but inhibited by blockade of the NF-kappaB, PI3K, and JAK-STAT pathways or the presence of neutralizing anti-IFN-beta. The catalytic function of the induced cell surface ART2.1 was strictly dependent on the presence of extracellular thiol-reducing cofactors, suggesting that in vivo activity of ART2.1-expressing macrophages may be potentiated in hypoxic or ischemic compartments. Consistent with the mutated art2a gene in C57BL/6 mice, LPS- or IFN-stimulated BMDM from this strain lacked expression of cell surface ART2 activity in the presence or absence of extracellular thiol reductants. Collectively, these studies identify ART2.1 as a new candidate for linking autocrine/paracrine activation of inflammatory macrophages to the release of NAD, a critical intracellular metabolite.
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PMID:Lipopolysaccharide, IFN-gamma, and IFN-beta induce expression of the thiol-sensitive ART2.1 Ecto-ADP-ribosyltransferase in murine macrophages. 1794 97

Interferons (IFNs) are pleiotropic cytokines responsible for inducing innate and adaptive immunities against a wide range of viruses and other microbial pathogens. In addition, IFNs also exert antitumor activities due to their antiproliferative, immunomodulatory, proapoptotic functions. In the last decades, the successful clinical application of IFNs for treatment of cancer, particularly leukemia, has improved the quality and longevity of life for many patients. The induction of tumor cell apoptosis by IFNs is believed to contribute, at least in part, to the beneficial effects. IFN subtypes, such as IFN-alpha, IFN-beta, and IFN-gamma, induce apoptosis through cell type-specific signaling pathways, and several putative IFN-stimulated genes (ISGs) with proapoptotic functions have been identified. Here, we analyzed the ability of IFN-alpha, IFN-beta, or IFN-gamma to induce apoptosis in several malignant hematologic cell lines. We found that treatment with IFN-gamma, but not IFN-alpha, or IFN-beta, specifically induces HL-60 leukemia cells to undergo apoptosis. Roughly 30% of HL-60 cells treated for 48 h with IFN-gamma, but not IFN-gamma, or IFN-beta, underwent apoptosis as monitored by annexin V labeling to determine changes in phosphatidylserine (PS) asymmetry and TUNEL assay to detect DNA fragmentation. Consistent with these results, treatment with IFN-gamma, but not IFN-alpha or IFN-beta, induced the release of cytochrome c, activation of caspase-3, and cleavage of poly (ADP-ribose) polymerase (PARP), a well-characterized caspase-3 substrate. Further investigation into the potential mechanism responsible for mitochondrial disruption revealed that treatment with IFN-gamma caused decreased levels of Bcl-2 and increased levels of Bak. This study thus provides the basis for additional research to uncover the molecular mechanism by which IFN-gamma regulates the expression of Bcl-2 family members in various cell types.
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PMID:IFN-gamma induces apoptosis in HL-60 cells through decreased Bcl-2 and increased Bak expression. 1827 2

Poly(ADP-ribose) polymerase-1 (PARP-1; EC 2.4.2.30) is an abundant nuclear protein that is involved in DNA repair, cell cycle control, programmed cell death and transcriptional regulation. It also plays critical roles in the pathogenesis of inflammatory disorders. Here we have performed a detailed analysis of the interplay between the apicomplexan parasite Toxoplasma gondii and host cell PARP and its consequences for the host-parasite relationship. Our results have shown that T. gondii significantly decreased PARP expression in its host cells within 10min of infection but that the amount of PARP normalized during prolonged infection. Importantly, down-regulation of PARP expression after infection abrogated the ADP-ribosylation of acceptor proteins in response to oxidative stress. Overexpression of PARP in RAW264.7 cells revealed that elevated amounts of PARP neither affected host cell invasion nor intracellular development of T. gondii in non-stimulated or IFN-gamma/LPS-stimulated monocytes/macrophages. Furthermore, measurements of the activities of effector caspases 3 and 7 indicated that the blockade of host cell apoptosis by T. gondii occurs independently of the inhibition of PARP after infection. These findings suggest that the prominent decrease of host cell PARP and poly(ADP-ribos)ylation after parasitic infection do not affect the intracellular development of T. gondii in vitro.
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PMID:Transient inhibition of poly(ADP-ribose) polymerase expression and activity by Toxoplasma gondii is dispensable for parasite-mediated blockade of host cell apoptosis and intracellular parasite replication. 1839 34

Deregulated apoptosis and suppressed tumour reactive immunity render tumour cells to grow amok in the host body. Traditionally used botanicals may offer potential anticancer chemo-immunotherapeutic leads. We report in this study a chemically standardised herbal formulation (WSF) of Withania somnifera possessing anticancer and Th1 immune up-regulatory activities. WSF produced cytotoxicity in a panel of human cancer cell lines in vitro. The molecular mechanism of cell cytotoxicity, IC(50) 48h approximately 20mug/ml, was investigated in HL-60, where it induced apoptosis by activating both intrinsic and extrinsic signalling pathways. It induced early generation of reactive nitrogen and oxygen species (RNOS), thus producing oxidative stress mediated mitochondrial membrane potential (MMP) loss leading to the release of cytochrome c, the translocation of Bax to mitochondria and apoptosis-inducing factor to the nuclei. These events paralleled the activation of caspase-9, -3 and PARP cleavage. WSF also activated caspase-8 through enhanced expression of TNF-R1 and DR-4, suggesting also the involvement of extrinsic pathway of apoptosis. WSF at 150mg/kg, i.p., inhibited >50% tumour growth in the mouse tumour models. In tumour-bearing mice, WSF inhibited the expression of pStat-3, with a selective stimulation of Th1 immunity as evidenced by enhanced secretion of IFN-gamma and IL-2. In parallel, it enhanced the proliferation of CD4(+)/CD8(+) and NK cells along with an increased expression of CD40/CD40L/CD80. In addition, WSF also enhanced T cell activation in camptothecin treated tumour-bearing mice. WSF being safe when given orally up to 1500mg/kg to rats for 6 months may be found useful in the management of malignancy by targeting at multiple pathways.
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PMID:Immune modulation and apoptosis induction: Two sides of antitumoural activity of a standardised herbal formulation of Withania somnifera. 1926 63

Nicotinamide phosphoribosyltransferase (Nampt) inhibitors such as FK866 are potent inhibitors of NAD(+) synthesis that show promise for the treatment of different forms of cancer. Based on Nampt upregulation in activated T lymphocytes and on preliminary reports of lymphopenia in FK866 treated patients, we have investigated FK866 for its capacity to interfere with T lymphocyte function and survival. Intracellular pyridine nucleotides, ATP, mitochondrial function, viability, proliferation, activation markers and cytokine secretion were assessed in resting and in activated human T lymphocytes. In addition, we used experimental autoimmune encephalomyelitis (EAE) as a model of T-cell mediated autoimmune disease to assess FK866 efficacy in vivo. We show that activated, but not resting, T lymphocytes undergo massive NAD(+) depletion upon FK866-mediated Nampt inhibition. As a consequence, impaired proliferation, reduced IFN-gamma and TNF-alpha production, and finally autophagic cell demise result. We demonstrate that upregulation of the NAD(+)-degrading enzyme poly-(ADP-ribose)-polymerase (PARP) by activated T cells enhances their susceptibility to NAD(+) depletion. In addition, we relate defective IFN-gamma and TNF-alpha production in response to FK866 to impaired Sirt6 activity. Finally, we show that FK866 strikingly reduces the neurological damage and the clinical manifestations of EAE. In conclusion, Nampt inhibitors (and possibly Sirt6 inhibitors) could be used to modulate T cell-mediated immune responses and thereby be beneficial in immune-mediated disorders.
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PMID:Catastrophic NAD+ depletion in activated T lymphocytes through Nampt inhibition reduces demyelination and disability in EAE. 1993 64

Naringenin, a flavonoid in grapefruits and citrus fruits, has been reported to exhibit anti-inflammatory and anti-oxidative activities. Contact hypersensitivity (CHS) is a T cell-mediated immune reaction, and the factors released from macrophages also contribute to this response. Previous studies showed that naringenin suppressed CHS by inhibiting activation and migration of macrophages. However, little is known about naringenin's effects on T lymphocytes. Our study indicated that naringenin potently suppressed picryl chloride (PCl)-induced contact hypersensitivity by inhibiting the proliferation and activation of T lymphocytes. In vitro, both of the activated hapten-specific T cells and the T cells stimulated with anti-CD3/anti-CD28 showed growth arrest after naringenin treatment. Furthermore, naringenin reduced CD69 (the protein level) and cytokines such as IL-2, TNF-alpha, and IFN-gamma (the mRNA level) expressions which highly expressed by activated T cells. Meanwhile, naringenin also induced T cell apoptosis by upregulation of Bax, Bad, PARP, cleaved-caspase 3 and downregulation of phosphorylated Akt, Bcl-2. These findings suggest that, besides its anti-inflammatory activities in macrophages, naringenin also showed inhibitory effects on the activation and proliferation of T cells to alleviate symptoms of contact hypersensitivity.
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PMID:A novel regulatory mechanism of naringenin through inhibition of T lymphocyte function in contact hypersensitivity suppression. 2047 63


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