Role of poly(ADP-ribose) glycohydrolase in the development of inflammatory bowel disease in mice

Salvatore Cuzzocrea, Emanuela Mazzon, Tiziana Genovese, Concetta Crisafulli, Woo Kee Min, Rosanna Di Paola, Carmelo Muià, Jia He Li, Giuseppe Malleo, Weizhen Xu, Edmond Massuda, Emanuela Esposito, Jie Zhang, Zhao Qi Wang

Research output: Contribution to journalArticle

Abstract

Poly(ADP-ribose) is synthesized from nicotinamide adenine dinucleotide (NAD) by poly(ADP-ribose) polymerase 1 (PARP-1) and degraded by poly(ADP-ribose) glycohydrolase (PARG). The aim of the present study was to examine the role of PARG in the development of experimental colitis. To address this question, we used an experimental model of colitis, induced by dinitrobenzene sulfonic acid (DNBS). Mice lacking the functional 110-kDa isoform of PARG (PARG110KO mice) were resistant to colon injury induced by DNBS. The mucosa of colon tissues showed reduction of myeloperoxidase activity and attenuated staining for intercellular adhesion molecule 1 and vascular cell adhesion molecule 1. Moreover, overproduction of proinflammatory factors TNF-α and IL-1β and activation of cell death signaling pathway, i.e., the FAS ligand, were inhibited in these mutant mice. Finally pharmacological treatment of WT mice with GPI 16552 and 18214, two novel PARG inhibitors, showed a significant protective effect in DNBS-induced colitis. These genetic and pharmacological studies demonstrate that PARG modulates the inflammatory response and tissue injury events associated with colitis and PARG may be considered as a novel target for pharmacological intervention for the pathogenesis.

Original languageEnglish (US)
Pages (from-to)90-105
Number of pages16
JournalFree Radical Biology and Medicine
Volume42
Issue number1
DOIs
StatePublished - Jan 1 2007
Externally publishedYes

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Keywords

  • Apoptosis
  • Colitis
  • IL-1β
  • Inflammation
  • PARG inhibitor
  • PARG110 deletion
  • TNF-α

ASJC Scopus subject areas

  • Medicine(all)
  • Toxicology
  • Clinical Biochemistry

Cite this

Cuzzocrea, S., Mazzon, E., Genovese, T., Crisafulli, C., Min, W. K., Di Paola, R., Muià, C., Li, J. H., Malleo, G., Xu, W., Massuda, E., Esposito, E., Zhang, J., & Wang, Z. Q. (2007). Role of poly(ADP-ribose) glycohydrolase in the development of inflammatory bowel disease in mice. Free Radical Biology and Medicine, 42(1), 90-105. https://doi.org/10.1016/j.freeradbiomed.2006.09.025