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A key role for poly(ADP-ribose) polymerase-1 activity during human dendritic cell maturation.
- Source :
-
Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2007 Jul 01; Vol. 179 (1), pp. 305-12. - Publication Year :
- 2007
-
Abstract
- 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-kappaB-dependent transactivation, we also report that phenanthridinone and thieno[2,3-c]isoquinolin-5-one impaired NF-kappaB 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.
- Subjects :
- Cell Differentiation drug effects
Cells, Cultured
DNA-Binding Proteins antagonists & inhibitors
DNA-Binding Proteins metabolism
Dendritic Cells drug effects
Down-Regulation drug effects
Down-Regulation immunology
Enzyme Activation drug effects
Enzyme Inhibitors pharmacology
Humans
Immunophenotyping
Interleukin-10 antagonists & inhibitors
Interleukin-10 biosynthesis
Interleukin-12 antagonists & inhibitors
Interleukin-12 biosynthesis
Lymphocyte Activation drug effects
Monocytes cytology
Monocytes enzymology
NF-kappa B antagonists & inhibitors
NF-kappa B metabolism
Poly (ADP-Ribose) Polymerase-1
Poly(ADP-ribose) Polymerase Inhibitors
Poly(ADP-ribose) Polymerases biosynthesis
Transcription Factor AP-1 antagonists & inhibitors
Transcription Factor AP-1 metabolism
p38 Mitogen-Activated Protein Kinases metabolism
Cell Differentiation immunology
Dendritic Cells cytology
Dendritic Cells enzymology
Poly(ADP-ribose) Polymerases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0022-1767
- Volume :
- 179
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Publication Type :
- Academic Journal
- Accession number :
- 17579050
- Full Text :
- https://doi.org/10.4049/jimmunol.179.1.305