A key role for poly(ADP-ribose) polymerase-1 activity during human dendritic cell maturation

• Published in: Journal of Immunology 2007-07, Vol.179 (1), p.305-312
• Main Authors: Aldinucci, Alessandra, Gerlini, Gianni, Fossati, Silvia, Cipriani, Giulia, Ballerini, Clara, Biagioli, Tiziana, Pimpinelli, Nicola, Borgognoni, Lorenzo, Massacesi, Luca, Moroni, Flavio, Chiarugi, Alberto
• Format: Article
• Language: English
• Subjects: Cell Differentiation - drug effects; Cell Differentiation - immunology; Cells, Cultured; Dendritic Cells - cytology; Dendritic Cells - drug effects; Dendritic Cells - enzymology; DNA-Binding Proteins - antagonists & inhibitors; DNA-Binding Proteins - metabolism; 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; p38 Mitogen-Activated Protein Kinases - metabolism; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases - biosynthesis; Poly(ADP-ribose) Polymerases - metabolism; Transcription Factor AP-1 - antagonists & inhibitors; Transcription Factor AP-1 - metabolism
• ISSN: 0022-1767; 1550-6606; 1365-2567
• DOI: 10.4049/jimmunol.179.1.305

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.