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The Role of Poly(ADP-ribose) Polymerase-1 in Rheumatoid Arthritis.

García S, Conde C - Mediators Inflamm. (2015)

Bottom Line: Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme with a crucial role in the maintenance of genomic stability.In addition to the role of PARP-1 in DNA repair, multiple studies have also demonstrated its involvement in several inflammatory diseases, such as septic shock, asthma, atherosclerosis, and stroke, as well as in cancer.In these diseases, the pharmacological inhibition of PARP-1 has shown a beneficial effect, suggesting that PARP-1 regulates their inflammatory processes.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Translational Immunology and Department of Rheumatology and Clinical Immunology, University Medical Center, Lundlaan 6, 3508 GA Utrecht, Netherlands.

ABSTRACT
Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme with a crucial role in the maintenance of genomic stability. In addition to the role of PARP-1 in DNA repair, multiple studies have also demonstrated its involvement in several inflammatory diseases, such as septic shock, asthma, atherosclerosis, and stroke, as well as in cancer. In these diseases, the pharmacological inhibition of PARP-1 has shown a beneficial effect, suggesting that PARP-1 regulates their inflammatory processes. In recent years, we have studied the role of PARP-1 in rheumatoid arthritis, as have other researchers, and the results have shown that PARP-1 has an important function in the development of this disease. This review summarizes current knowledge on the effects of PARP-1 in rheumatoid arthritis.

No MeSH data available.


Related in: MedlinePlus

Effect of PARP-1 on the TNF-α induced production of inflammatory mediators in RA FLS. TNF-α stimulation induces the activation and the translocation to the nucleus of the transcription factors NF-κB and AP-1. In the nucleus, PARP-1 enzymatic activity and/or direct protein interaction enhances the transcriptional activity of both NF-κB and AP-1, leading to the production of inflammatory mediators.
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Related In: Results  -  Collection


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fig1: Effect of PARP-1 on the TNF-α induced production of inflammatory mediators in RA FLS. TNF-α stimulation induces the activation and the translocation to the nucleus of the transcription factors NF-κB and AP-1. In the nucleus, PARP-1 enzymatic activity and/or direct protein interaction enhances the transcriptional activity of both NF-κB and AP-1, leading to the production of inflammatory mediators.

Mentions: To extend the knowledge about the role of PARP-1 in rheumatoid arthritis, our group analysed the effect of PARP inhibition on the cell proliferation, production of inflammatory mediators, and activation of molecular pathways in the RA FLS. The results showed that PARP-1 inhibition reduced the FLS proliferation and the TNF-induced IL-6, IL-8, MCP-1, RANTES, and MMP-3 production. PARP-1 suppression by siRNA confirmed the reduction of the production of the TNF-induced inflammatory mediators, suggesting that the reduced inflammatory response we observed was due to the inhibition of poly(ADP-ribosil)ation and not to effects other than the inhibition of the PARP function. Moreover, the results also suggest that PARP-1 is the PARP family member responsible for this reduction. Indeed, in this work we have suggested that the reductions in the production of inflammatory mediators and proliferation are most likely due to the reduced activation of NF-κB and AP-1, as we observed a partially impaired NF-κB and AP-1 binding activity after the treatment with the PARP inhibitors or after the siRNA PARP-1 transfection (Figure 1) [38].


The Role of Poly(ADP-ribose) Polymerase-1 in Rheumatoid Arthritis.

García S, Conde C - Mediators Inflamm. (2015)

Effect of PARP-1 on the TNF-α induced production of inflammatory mediators in RA FLS. TNF-α stimulation induces the activation and the translocation to the nucleus of the transcription factors NF-κB and AP-1. In the nucleus, PARP-1 enzymatic activity and/or direct protein interaction enhances the transcriptional activity of both NF-κB and AP-1, leading to the production of inflammatory mediators.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4539103&req=5

fig1: Effect of PARP-1 on the TNF-α induced production of inflammatory mediators in RA FLS. TNF-α stimulation induces the activation and the translocation to the nucleus of the transcription factors NF-κB and AP-1. In the nucleus, PARP-1 enzymatic activity and/or direct protein interaction enhances the transcriptional activity of both NF-κB and AP-1, leading to the production of inflammatory mediators.
Mentions: To extend the knowledge about the role of PARP-1 in rheumatoid arthritis, our group analysed the effect of PARP inhibition on the cell proliferation, production of inflammatory mediators, and activation of molecular pathways in the RA FLS. The results showed that PARP-1 inhibition reduced the FLS proliferation and the TNF-induced IL-6, IL-8, MCP-1, RANTES, and MMP-3 production. PARP-1 suppression by siRNA confirmed the reduction of the production of the TNF-induced inflammatory mediators, suggesting that the reduced inflammatory response we observed was due to the inhibition of poly(ADP-ribosil)ation and not to effects other than the inhibition of the PARP function. Moreover, the results also suggest that PARP-1 is the PARP family member responsible for this reduction. Indeed, in this work we have suggested that the reductions in the production of inflammatory mediators and proliferation are most likely due to the reduced activation of NF-κB and AP-1, as we observed a partially impaired NF-κB and AP-1 binding activity after the treatment with the PARP inhibitors or after the siRNA PARP-1 transfection (Figure 1) [38].

Bottom Line: Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme with a crucial role in the maintenance of genomic stability.In addition to the role of PARP-1 in DNA repair, multiple studies have also demonstrated its involvement in several inflammatory diseases, such as septic shock, asthma, atherosclerosis, and stroke, as well as in cancer.In these diseases, the pharmacological inhibition of PARP-1 has shown a beneficial effect, suggesting that PARP-1 regulates their inflammatory processes.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Translational Immunology and Department of Rheumatology and Clinical Immunology, University Medical Center, Lundlaan 6, 3508 GA Utrecht, Netherlands.

ABSTRACT
Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme with a crucial role in the maintenance of genomic stability. In addition to the role of PARP-1 in DNA repair, multiple studies have also demonstrated its involvement in several inflammatory diseases, such as septic shock, asthma, atherosclerosis, and stroke, as well as in cancer. In these diseases, the pharmacological inhibition of PARP-1 has shown a beneficial effect, suggesting that PARP-1 regulates their inflammatory processes. In recent years, we have studied the role of PARP-1 in rheumatoid arthritis, as have other researchers, and the results have shown that PARP-1 has an important function in the development of this disease. This review summarizes current knowledge on the effects of PARP-1 in rheumatoid arthritis.

No MeSH data available.


Related in: MedlinePlus