Poly(ADP-ribose) polymerase in the immune system: Focus on reactive nitrogen intermediates and cell death

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Macrophages were among the first cell types identified as a source of nitric oxide (NO) produced by the inducible nitric oxide synthase (iNOS). 1-5 NO production represents a major cytotoxic mechanism utilized by macrophages to kill certain pathogens and tumor cells. 4-8 Although NO is a free radical capable of inhibiting the respiratory chain, 5,8 inactivating enzymes, 9,10 peroxidating lipids, 11-13 and causing cytotoxicity, 4,5 cell damage associated with increased NO production is more likely to be mediated by NO-derived oxidants such as peroxynitrite than by NO per se. 14 Peroxynitrite (ONOO ) is a binary toxin assembled when NO and superoxide (O 2 ) are produced together. 14 Peroxynitrite is a very potent inducer of DNA single-strand breaks 15-18 and thus poly(ADP-ribose) polymerase (PARP) activation. 18-20 Because activated macrophages upregulate iNOS and produce large amounts of NO in parallel with the overproduction of superoxide in a process called “oxidative burst,” macrophage activation provides ideal conditions for peroxynitrite formation. Indeed, activated macrophages have been shown to produce ONOO -. 21 Macrophages and related cell types (e.g., dendritic cells) are present in all lymphoid organs where they sample antigens from the lymph and the bloodstream and present antigens to T lymphocytes. Activated T lymphocytes in turn secrete interferon γ (IFN γ), which is a potent activator of macrophages. Thus, during antigen presentation cross-activation between antigen-presenting cells (APC) and T cells may result in NO production, peroxynitrite formation, and PARP activation. Indeed, NO production by APCs (Langerhans cells, dendritic cells) and modulation of T-cell function by APC-derived NO has been reported in the literature. 22-25 Peroxynitrite-induced PARP activation may occur in the NO-producing cell or in cells localized in the vicinity of the source of NO. We have selected the thymus as a primary lymphoid organ and investigated (1) whether NO is produced in the thymus, (2) whether intrathymic NO production results in peroxynitrite formation in the thymus, and (3) whether PARP activation occurs in thymocytes. Moreover, we have extensively investigated the in vitro effect of peroxynitrite on thymocytes as a model cell type and studied how PARP activation affects the mode of peroxynitrite-induced cell death.

Original languageEnglish
Title of host publicationCell Death
Subtitle of host publicationThe Role of Poly (ADP-ribose) Polymerase
PublisherCRC Press
Number of pages36
ISBN (Electronic)9781420038897
ISBN (Print)0849322677, 9780849322679
Publication statusPublished - Jan 1 2000

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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