A poly(ADP‐ribose) polymerase haplotype spanning the promoter region confers susceptibility to rheumatoid arthritis

Pascual, María José; López–Nevot, Miguel A.; Cáliz, Rafael; Ferrer, Miguel; Balsa, Alejandro; Pascual‐Salcedo, Dora; Martı́n, Javier

doi:10.1002/art.10864

Cited by 41 publications

(53 citation statements)

References 15 publications

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“…In addition to the beneficial effects of PARP inhibitors and protection provided by knockout phenotypes, the role of PARPs in inflammation is also indicated by association of certain PARP-1 promoter haplotypes and SNPs with diseases. Such associations have been reported for systemic lupus erythematosus [76], autoimmune nephritis [76] or rheumathois arthritis [77] further supporting a possible link between PARP-1 and autoimmune inflammation.…”

Section: Inflammatory Diseases Mediated By Poly(adp-ribose) Polymerasessupporting

confidence: 58%

Role of poly(ADP‐ribose) polymerases in the regulation of inflammatory processes

Bai

Virág

2012

FEBS Letters

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a b s t r a c t PARP enzymes influence the immune system at several key points and thus modulate inflammatory diseases. PARP enzymes affect immune cell maturation and differentiation and regulate the expression of inflammatory mediators such as cytokines, chemokines, inducible nitric oxide synthase and adhesion molecules. Moreover, PARP enzymes are key regulators of cell death during inflammationrelated oxidative and nitrosative stress. Here we provide an overview of the different inflammatory diseases regulated by PARP enzymes.

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Section: Inflammatory Diseases Mediated By Poly(adp-ribose) Polymerasessupporting

confidence: 58%

Role of poly(ADP‐ribose) polymerases in the regulation of inflammatory processes

Bai

Virág

2012

FEBS Letters

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“…The length of the CA microsatellite in the promoter has not only been implicated in transcription of PARP-1 but has also been (Pascual et al, 2003). Previous studies showed that a long CA microsatellite is related to autoimmune diseases, namely, rheumatoid arthritis and coeliac disease (Pascual et al, 2003;Rueda et al, 2005). This evidence implicates PARP-1 primarily in inflammatory processes leading to the development of immunological disorders, but these may also lead to promotion and development of cancer by NF-kB dependent or independent mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, due to the small sample number, we did not find any significant correlation between PARP-1 activity and T2444C genotype ( Figure 2C). The length of the CA microsatellite in the promoter has not only been implicated in transcription of PARP-1 but has also been (Pascual et al, 2003). Previous studies showed that a long CA microsatellite is related to autoimmune diseases, namely, rheumatoid arthritis and coeliac disease (Pascual et al, 2003;Rueda et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…We therefore investigated the length of this microsatellite repeat sequence in our cell line panel. As established earlier (Pascual et al, 2003), we grouped the CA microsatellite into two alleles: S (short)À(CA) 11À12 and L (long)À(CA) 13À20 . We found the following genotype frequencies: 61% SS (TK-6, HS-5, MDA-MB-231, MCF-7, Pre B697, Naml6, CCRF-CEM, K562, TR14, NB1691, Jurkat), 28% SL (ML-1, T47D, Molt-4, HL-60, SK-N-BE2C), 11% LL (Raji, LoVo) ( Table 1).…”

Section: Parp Active Site Snp T2444c (Val762ala)mentioning

confidence: 99%

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Poly(ADP-ribose) polymerase-1 polymorphisms, expression and activity in selected human tumour cell lines

et al. 2009

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BACKGROUND: Poly(ADP-ribose) polymerase-1 (PARP-1) is a DNA-binding enzyme activated by DNA breaks and involved in DNA repair and other cellular processes. Poly(ADP-ribose) polymerase activity can be higher in cancer than in adjacent normal tissue, but cancer predisposition is reported to be greater in individuals with a single-nucleotide polymorphism (SNP) V762A (T2444C) in the catalytic domain that reduces PARP-1 activity. METHODS: To resolve these divergent observations, we determined PARP-1 polymorphisms, PARP-1 protein expression and activity in a panel of 19 solid and haematological, adult and paediatric human cancer cell lines. RESULTS: There was a wide variation in PARP activity in the cell line panel (coefficient of variation, CV ¼ 103%), with the lowest and the highest activity being 2460 pmol PAR/10 6 (HS-5 cells) and 85 750 pmol PAR/10 6 (NGP cells). Lower variation (CV ¼ 32%) was observed in PARP-1 protein expression with the lowest expression being 2.0 ng mg À1 (HS-5 cells) and the highest being 7.1 ng mg À1 (ML-1 cells). The mean activity in the cancer cells was 45-fold higher than the mean activity in normal human lymphocytes and the PARP-1 protein levels were 23-fold higher. CONCLUSIONS: Surprisingly, there was no significant correlation between PARP activity and PARP-1 protein level or the investigated polymorphisms, T2444C and CA.

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“…Genetic variants within this region may therefore affect PARP-1 expression and inducibility. In this context, it is puzzling that specific haplotypes of parp-1 promoter confer higher risk of autoimmune disorders such as rheumatoid arthritis (56), celiac disease (57), and systemic lupus erythematosus (58). It is therefore tempting to speculate that induction of PARP-1 in DCs and/or other immune cells participates in development of autoimmunity.…”

Section: Discussionmentioning

confidence: 99%

A Key Role for Poly(ADP-Ribose) Polymerase-1 Activity during Human Dendritic Cell Maturation

Aldinucci¹,

Gerlini

Fossati³

et al. 2007

The Journal of Immunology

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Poly(ADP-ribose) (PAR) polymerase (PARP)-1 is a nuclear enzyme regulating protein that functions by targeting PAR chains. Besides its classic role in DNA repair, PARP-1 is emerging as a key transcriptional regulator in different cell types including the immune ones. In this study, we investigated the role of PARP-1 in human dendritic cell (DC) function. We report that both PARP-1 mRNA and protein levels significantly increased during in vitro DC differentiation from monocytes. Of note, inhibitors of PARP-1 such as phenanthridinone and thieno[2,3-c]isoquinolin-5-one reduced expression of CD86 and CD83 in a concentration-dependent manner, having no effects on expression of CD80 and HLA-DR in mature DCs. In the same cultures, PARP-1 inhibitors also reduced production of IL-12 and IL-10. Addition of exogenous IL-12 to the culture medium partially restored CD86 expression in DCs exposed to PARP-1 inhibitors. In line with the role of PAR formation in NF-κB-dependent transactivation, we also report that phenanthridinone and thieno[2,3-c]isoquinolin-5-one impaired NF-κB and AP-1 subunit DNA binding activity in cellular extract of activated DCs. Finally, we show that PARP-1 inhibitors reduced the T cell allostimulatory activity of mature DCs, and that this reduction was prevented when DCs matured in the presence of PARP-1 inhibitors plus IL-12. Of note, nonproliferating T cells exposed to PARP-1 inhibitor-challenged DCs could undergo efficient proliferation when exposed to a subsequent activation stimulus such as anti-CD3 plus anti-CD-28. Together, data provide evidence for a key role of PARP-1 and poly ADP-ribosylation in DC immunocompetence and underscore the relevance of PARP-1 inhibitors to treatment of immune disorders.

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A poly(ADP‐ribose) polymerase haplotype spanning the promoter region confers susceptibility to rheumatoid arthritis

Cited by 41 publications

References 15 publications

Role of poly(ADP‐ribose) polymerases in the regulation of inflammatory processes

Role of poly(ADP‐ribose) polymerases in the regulation of inflammatory processes

Poly(ADP-ribose) polymerase-1 polymorphisms, expression and activity in selected human tumour cell lines

A Key Role for Poly(ADP-Ribose) Polymerase-1 Activity during Human Dendritic Cell Maturation

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