Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.4.2.30 (PARP)
13,611 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The interleukin 4 (IL 4) receptor is expressed on various cells of the immune system, including T and B lymphocytes, macrophages and mast cells. We have constructed a recombinant protein, DAB389-mIL 4, that is composed of the enzymatically active and membrane translocation domains of diphtheria toxin fused to murine IL 4. We demonstrate that this fusion toxin selectively inhibits protein synsthesis in eukaryotic cells which express the murine IL 4 receptor. The cytotoxic potency of this fusion toxin is shown to be directly proportional to the reported number of IL 4 receptors on the surface of target cells. Since the action of DAB389-mIL 4 can be blocked with either excess mIL 4 or antibody to mIL 4, we conclude that its entry into target cells is mediated through the mIL 4 receptor. A mutant form of DAB389-mIL 4, DA(197)B389-mIL 4, in which the fragment A-associated ADP-ribosyltransferase is inactive, is not cytotoxic to murine IL 4 receptor-bearing cells. Finally, we demonstrate that DAB389-mIL 4 administered subcutaneously to DBA/2 mice results in suppression of delayed-type hypersensitivity (DTH); whereas, the non-toxic DA(197)B389-mIL 4 fails to dampen the DTH response.
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PMID:Interleukin 4 receptor targeted cytotoxicity: genetic construction and in vivo immunosuppressive activity of a diphtheria toxin-related murine interleukin 4 fusion protein. 167 15

Previous studies suggest that heavy chain isotype switch (S) recombination is directed by cytokine-induced transcription of the unrearranged CH gene before recombination. In studies aimed at identifying other signaling pathways that promote switching, we discovered that inhibitors of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) increase LPS-induced switching to IgA in the B cell lymphoma 1.29 mu and to IgG1 in LPS + IL-4-treated splenic B cells. PARP, which binds to and is activated by DNA strand breaks, catalyzes the removal of ADP-ribose from NAD+ and poly(ADP-ribosylation) of chromatin-associated acceptor proteins. This enzyme is believed to function in cellular processes involving DNA strand breaks as well as in modulating chromatin structure. In 1.29 mu cells, PARP inhibitors increase IgA switching by day 2 and cause a fivefold increase in switching on day 3 as assayed by immunofluorescence microscopy. In spleen B cells, the PARP inhibitor nicotinamide increases IgG1 switching by about twofold. Nicotinamide also causes a reduced intensity of hybridization of C mu- and C alpha-specific probes to genomic DNA fragments containing the expressed VDJ-C mu and the unrearranged S alpha-C alpha segments, respectively, in 1.29 mu cells, indicating that PARP inhibition increases rearrangement of these fragments. Induction of switching by PARP inhibitors is not mimicked by treatment with cAMP analogues or reduced by inhibitors of protein kinase A. Induction of switching by PARP inhibitors does not appear to involve increased levels of transcription of the unrearranged C alpha gene.
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PMID:Inhibitors of poly(ADP-ribose) polymerase increase antibody class switching. 825 3

Pertussis toxin (PT) is a major virulence factor of Bordetella pertussis which exerts a range of effects on the immune system, including the enhancement of IgE, IgA and IgG production, delayed-type hypersensitivity reactions, and the induction of experimental autoimmune diseases. However, the mechanism by which PT mediates adjuvanticity remains to be defined. In this investigation we have shown that PT can potentiate antigen-specific T cell proliferation and the secretion of IFN-gamma, IL-2, IL-4 and IL-5 when injected with foreign antigens. A chemically detoxified PT and a genetic mutant with substitutions/deletions in the S-1 and B oligomer components that abrogate enzymatic and binding activity displayed no adjuvant properties. In contrast, a non-toxic S-1 mutant devoid of enzymatic activity but still capable of receptor binding retained its adjuvanticity, augmenting the activation of both Th1 and Th2 subpopulations of T cells. In an attempt to address the mechanism of T cell activation, we found that PT stimulated the production of IFN-gamma and IL-2 by naive T cells and IL-1 by macrophages. Therefore potentiation of distinct T cell subpopulations may have resulted in part from the positive influence of IFN-gamma on the development of Th1 cells and the co-stimulatory role of IL-1 for Th2 cells. Furthermore, PT augmented expression of the co-stimulatory molecules B7-1 and B7-2 on macrophages and B cells, and CD28 on T cells, suggesting that the adjuvant effect may also be associated with facilitation of the second signal required for maximal T cell activation. This study demonstrates that the immunopotentiating properties of PT are largely independent of ADP-ribosyltransferase activity, but are dependent on receptor binding activity and appear to involve enhanced activation of T cells.
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PMID:Pertussis toxin potentiates Th1 and Th2 responses to co-injected antigen: adjuvant action is associated with enhanced regulatory cytokine production and expression of the co-stimulatory molecules B7-1, B7-2 and CD28. 964 13

We tested the effects of hydroxychloroquine (HCQ), an anti-rheumatic drug, on the viability of chronic lymphocytic leukemia (CLL) cells. HCQ induced a decrease in cell viability in a dose- and time-dependent manner. The mean LC50 calculated for the cells of 20 patients was 32 +/- 7 microg/ml (range, 10-75 microg/ml). We observed a large increase in apoptotic cell number after 24 h of incubation with 50 microg/ml HCQ (55 +/- 6 vs. 23 +/- 3% in medium alone, p < 0.001). Indeed, HCQ in leukemic cells induced the features of apoptosis (cell shrinkage, decrease in mitochondrial transmembrane potential, phosphatidylserine externalization, chromatin condensation and DNA fragmentation). HCQ had marked selective cytotoxicity when compared with normal blood mononuclear cells, in which the LC50 was >100 microg/ml at 24 h. HCQ induced the proteolytic cleavage of poly(ADP(adenosine 5'-diphosphate)ribose) polymerase (PARP) and increased the activity of caspase-3. The expression of bcl-2 and bax proteins was significantly modified after incubation with the drug and HCQ activity against CLL cells occurred independently of the presence of IL-4, sCD40L and bone marrow stromal cells.
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PMID:Hydroxychloroquine-induced apoptosis of chronic lymphocytic leukemia involves activation of caspase-3 and modulation of Bcl-2/bax/ratio. 1214 91

Bordetella pertussis toxin (PTX), a key component of acellular pertussis vaccines, is known to be endowed with adjuvant properties. In experiments designed to get insights into the interactions between PTX and circulating immune cells, we first observed that addition of PTX to adult whole blood induced the release of IL-12 and TNF-alpha as well as maturation of myeloid dendritic cells (DC). These effects were still present with a toxin mutant devoid of ADP-ribosyltransferase activity but not with a formaldehyde-inactivated toxin. These findings indicate that cytokine production and DC maturation require the intact structure of PTX but not its enzymatic activity. Secondly, studies on DC generated in vitro by culturing monocytes with IL-4 and GM-CSF showed that PTX directly stimulates MHC class II and costimulatory molecules up-regulation, cytokine synthesis and NF-kappa B activation. Finally, comparison of data obtained in adult vs. cord blood revealed deficient responses of neonatal DC to PTX. These data suggest new applications of PTX and PTX mutants as vaccine adjuvants.
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PMID:Bordetella pertussis toxin induces the release of inflammatory cytokines and dendritic cell activation in whole blood: impaired responses in human newborns. 1238 32

Human B cells isolated from peripheral blood were activated and induced to proliferate by either Epstein-Barr virus (EBV) or the T cell-derived mitogens CD40 ligand (CD40L) plus interleukin (IL)-4. Although both populations initially proliferated as B-blasts, significant differences were revealed over a longer period. EBV infection resulted in continuously proliferating lymphoblastoid cell lines (LCLs), whereas most of the CD40L/IL-4-stimulated B cells had a finite proliferative lifespan of 3-4 weeks. Cell cycle analysis, trypan blue staining and Western blot analysis for cleavage of poly(ADP-ribose) polymerase (PARP) all demonstrated that the decrease in proliferation in CD40L/IL-4-stimulated B cells is not due to cell death. Instead, these cells arrest, accumulate in G(0)/G(1) and undergo alterations in cell surface marker expression, cellular morphology and immunoglobulin production, all consistent with plasmacytoid differentiation. In contrast, B cells infected with EBV continued to proliferate and retained a blast-like phenotype. Differences in both cytokine production and the expression of cell cycle regulators were identified between the two B-cell populations, which might contribute to the differentiation of the CD40L/IL-4-stimulated B cells and suggest potential mechanisms by which EBV may overcome this. The study has also identified a window of opportunity during which a comparison of isogenic populations of EBV- and mitogen-driven B blasts can be made.
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PMID:Proliferation and differentiation in isogenic populations of peripheral B cells activated by Epstein-Barr virus or T cell-derived mitogens. 1503 31

It is unknown whether IL-4 induces apoptosis in oral cavity cancer (OCC) cells and, if so, what the mediator of this apoptosis is. Therefore, this study investigated whether apoptosis of OCC cells is induced by IL-4 and whether 15-lipoxygenase-1 (15-LO-1), induced by IL-4, is the mediator of this apoptosis. SCC 1483 oral cavity cancer cells were used in these experiments, and flow cytometry and PARP cleavage were used to examine apoptosis. At an IL-4 dosage that inhibited 50% of cell proliferation, apoptosis was observed, and this apoptosis was inhibited by 2.2 microM caffeic acid (CA). 15-LO-1 mRNA expression was observed beginning at 8 h after treatment with IL-4, and apoptosis increased after 24 h treatment with IL-4. In this apoptosis, the caspase cascade was not involved. In summary, IL-4 induced apoptosis in SCC 1483 OCC cells, and 15-LO-1, induced by IL-4, may mediate this apoptotic pathway.
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PMID:15-Lipoxygenase-1 induced by interleukin-4 mediates apoptosis in oral cavity cancer cells. 1647 53

We recently used a murine model of allergic airway inflammation to show that poly(ADP-ribose) polymerase-1 (PARP-1) plays an important role in the pathogenesis of asthma-related lung inflammation. In this study, we show that PARP-1 inhibition, by a novel inhibitor (TIQ-A) or by gene deletion, prevented eosinophilic infiltration into the airways of OVA-challenged mice. Such impairment of eosinophil recruitment appeared to take place after IgE production. OVA challenge of wild-type mice resulted in a significant increase in IL-4, IL-5, IL-10, IL-13, and GM-CSF secretions. Although IL-4 production was moderately affected in OVA-challenged PARP-1(-/-) mice, the production of IL-5, IL-10, IL-13, and GM-CSF was completely inhibited in ex vivo OVA-challenged lung cells derived from these animals. A single TIQ-A injection before OVA challenge in wild-type mice mimicked the latter effects. The marked effect PARP-1 inhibition exerted on mucus production corroborated the effects observed on the Th2 response. Although PARP-1 inhibition by gene knockout increased the production of the Th1 cytokines IL-2 and IL-12, the inhibition by TIQ-A exerted no effect on these two cytokines. The failure of lung cells derived from OVA-challenged PARP-1(-/-) mice to synthesize GM-CSF, a key cytokine in eosinophil recruitment, was reestablished by replenishment of IL-5. Furthermore, intranasal administration of IL-5 restored the impairment of eosinophil recruitment and mucus production in OVA-challenged PARP-1(-/-) mice. The replenishment of either IL-4 or IgE, however, did not result in such phenotype reversals. Altogether, these results suggest that PARP-1 plays a critical role in eosinophil recruitment by specifically regulating the cascade leading to IL-5 production.
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PMID:Poly(ADP-ribose) polymerase-1 inhibition prevents eosinophil recruitment by modulating Th2 cytokines in a murine model of allergic airway inflammation: a potential specific effect on IL-5. 1705 81

ADP-ribosylation is a reversible posttranslational modification mediated by poly-ADP-ribose polymerase (PARP). The results of recent studies demonstrate that ADP-ribosylation contributes to transcription regulation. Here, we report that transcription factor NFAT binds to and is ADP-ribosylated by PARP-1 in an activation-dependent manner. Mechanistically, ADP-ribosylation increases NFAT DNA binding. Functionally, NFAT-mediated interleukin-2 (IL-2) expression was reduced in T cells upon genetic ablation or pharmacological inhibition of PARP-1. Parp-1(-/-) T cells also exhibit reduced expression of other NFAT-dependent cytokines, such as IL-4. Together, these results demonstrate that ADP-ribosylation mediated by PARP-1 provides a molecular switch to positively regulate NFAT-dependent cytokine gene transcription. These results also imply that, similar to the effect of calcineurin inhibition, PARP-1 inhibition may be beneficial in modulating immune functions.
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PMID:Regulation of transcription factor NFAT by ADP-ribosylation. 1829 89

Poly(ADP-ribos)ylation is one of the longest-known but most enigmatic posttranslational modifications transducing specific signals. The enzyme responsible for the majority of poly(ADP-ribose) polymerization in cells, PARP-1, promotes DNA repair but also mediates a caspase-independent form of apoptosis in response to stressors such as irradiation. However, the biologic function of most other PARPs is not known. Macro-PARPs constitute one branch of the large family of PARP-like proteins also designated as B aggressive lymphoma proteins (BAL1, 2a/2b, 3, or PARP-9, PARP-14, and PARP-15). To elucidate biologic role(s) of a BAL-family macro-PARP, we analyzed mice deficient in PARP-14, a binding partner of the IL-4-induced transcription factor Stat6. We show here that PARP-14 plays a fundamental role mediating protection against apoptosis in IL-4-treated B cells, including that after DNA damage, and mediates IL-4 effects on the levels of gene products that regulate cell survival, proliferation, and lymphomagenesis. Collectively, the results establish that PARP-14 mediates regulation of gene expression and lymphocyte physiology by IL-4 and has a function distinct from PARP-1. Furthermore, the findings suggest mechanisms by which BAL-family proteins might influence pathologic processes involving B lymphocytes.
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PMID:PARP-14, a member of the B aggressive lymphoma family, transduces survival signals in primary B cells. 1914 89


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