Regulation of components of the inflammatory response by 5-iodo-6-amino-1,2-benzopyrone, an inhibitor of poly(ADP-ribose) synthetase and pleiotropic modifier of cellular signal pathways

Csaba Szabó, Hector R. Wong, Pal I. Bauer, Eva Kirsten, Michael O'Connor, Basilia Zingarelli, Jerome Mendeleyev, György Haskó, E. Sylvester Vizi, Andrew L. Salzman, Ernest Kun

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

Chronic inflammation is known to facilitate carcinogenic transformation in various tissues. 5-iodo-6-amino-1,2-benzopyrone (INH2BP), a novel inhibitor of the nuclear enzyme poly(ADP-ribose) polymerase (pADPRT) has recently been shown to regulate a variety of cellular signal transduction pathways and to abrogate in vivo tumorigenicity by a Ha-ras transfected endothelial cell line. Here we have investigated the effect of INH2BP on the activation by endotoxin (bacterial lipopolysaccharide, LPS) on the production of the inflammatory mediators tumor necrosis factor a (TNFα), interleukin-10 (IL-10) and interleukin-6 (IL-6), nitric oxide (NO) and prostaglandins in vitro and in vivo. In addition, we studied the effect of INH2BP on the activation of mitogen-activated protein kinase (MAP kinase) and nuclear factor κB (NF-κB) in vitro. In cultured J774 and RAW 264.7 macrophages, LPS induced the production of prostaglandin metabolites, the release of TNF and the expression of the inducible isoform of NO synthase (iNOS). The production of prostaglandins and of NO were inhibited by INH2BP in a dose-dependent manner, while the short-term release of TNFα was unaffected. INH2BP markedly suppressed LPS-mediated luciferase activity in RAW cells transiently transfected with a full length (-1,592 bp) murine macrophage iNOS promoter-luciferase construct, but not in a deletional construct consisting of -367 bp. In vivo, INH2BP pretreatment inhibited the induction of iNOS by LPS in rats, did not affect the LPS-induced TNF and IL-6 response, but enhanced LPS-induced IL-10 production. INH2BP pretreatment markedly improved the survival of mice in a lethal model of endotoxin shock. Our results demonstrate that INH2BP has potent anti-inflammatory actions in vitro and in vivo.

Original languageEnglish
Pages (from-to)1093-1101
Number of pages9
JournalInternational journal of oncology
Volume10
Issue number6
DOIs
Publication statusPublished - 1997

Keywords

  • Cyclooxygenase
  • Endotoxin
  • MAP kinase
  • Nitric oxide
  • Nuclear factor κB
  • Prostaglandins
  • Septic shock
  • Superoxide
  • Tumor necrosis factor

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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