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First published on June 30, 2004; DOI: 10.1124/mol.104.000968

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Received for publication April 1, 2004.
Revised June 29, 2004.
Accepted for publication June 30, 2004.

Inhibition of poly(ADP-ribose) glycohydrolase by gallotannin selectively up-regulates expression of pro-inflammatory genes

Elena Rapizzi 1, Silvia Fossati 1, Flavio Moroni 1, Alberto Chiarugi 1*

1 University of Florence

* Address correspondence to: E-mail: alberto.chiarugi{at}unifi.it

Abstract

Poly(ADP-ribose)-polymerase-1 (PARP-1) and poly(ADP-ribose) (PAR) are emerging key regulators of chromatin superstructure and transcriptional activation. Accordingly, both genetic inactivation of PARP-1 and pharmacological inhibition of PAR formation impair expression of several genes, including those of the inflammatory response. In this study, we asked whether poly(ADP-ribose) glycohydrolase (PARG), the sole de-poly(ADP-ribosyl)ating enzyme identified so far, also regulates gene expression. We report the novel finding that inhibition of PARG by gallotannin triggered nuclear accumulation of PAR and concomitant PAR-dependent expression of iNOS and COX-2, but not of IL-1{beta} and TNF-{alpha}, in cultured RAW 264.7 macrophages. Remarkably, silencing of PARG by means of siRNA selectively impaired gallotannin-induced expression of iNOS and COX-2. Consistent with a PAR-dependent transcriptional activation, increases of iNOS and COX-2 transcripts were not due to activation of transcription factors such as NF-{kappa}B, AP-1, STAT-1 or IRF-1, nor to mRNA stabilization. Overall, data provide the first evidence that pharmacological inhibition of PARG leads to PAR-dependent alteration of gene expression profiles in macrophages.


Key words: Nitric oxide synthases, Transcriptional coactivators, DNA damage and repair, Cyclooxygenases


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