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A Key Role for Poly(ADP-Ribose) Polymerase-1 Activity during Human Dendritic Cell Maturation¹

Alessandra Aldinucci, Gianni Gerlini^,, Silvia Fossati^*, Giulia Cipriani^*, Clara Ballerini, Tiziana Biagioli, Nicola Pimpinelli, Lorenzo Borgognoni, Luca Massacesi, Flavio Moroni^* and Alberto Chiarugi^2,*

^* Department of Pharmacology, Department of Neurological and Psychiatric Sciences, and Department of Dermatological Sciences, University of Florence, and Plastic Surgery Unit, Melanoma Referral Center, Santa Maria Annunziata Hospital, Florence, Italy

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-B-dependent transactivation, we also report that phenanthridinone and thieno[2,3-c]isoquinolin-5-one impaired NF-B 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from Associazione Italiana Sclerosi Multipla, The Italian Ministry of Scientific Research, and Ente Cassa di Risparmio di Firenze.

² Address correspondence and reprint requests to Dr. Alberto Chiarugi, Department of Pharmacology, University of Florence, Viale Pieraccini 6, 50139 Firenze, Italy. E-mail address: alberto.chiarugi{at}unifi.it

³ Abbreviations used in this paper: PAR, poly(ADP-ribose); PARP, PAR polymerase; DC, dendritic cell; PHE, phenanthridinone; TIQ-A, thieno[2,3-c]isoquinolin-5-one.

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