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 Szabo, H. R. Wong, P. I. Bauer, E. Kirsten, M. O'Connor, B. Zingarelli, J. Mendeleyev, G. Hasko, E. S. Vizi, A. L. Salzman, E. Kun

Research output: Contribution to journalArticle

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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 α (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 xB (NF-xB) 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. INH 1/4 BP 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 (US)
Pages (from-to)1093-1101
Number of pages9
JournalInternational Journal of Oncology
Volume10
Issue number6
StatePublished - 1997
Externally publishedYes

Fingerprint

Poly Adenosine Diphosphate Ribose
Ligases
Lipopolysaccharides
Signal Transduction
Tumor Necrosis Factor-alpha
Prostaglandins
Protein Isoforms
Luciferases
Endotoxins
Nitric Oxide Synthase
Interleukin-10
Interleukin-6
Nitric Oxide
Macrophages
Poly(ADP-ribose) Polymerases
Enzyme Inhibitors
Nitric Oxide Synthase Type II
Mitogen-Activated Protein Kinases
5-iodo-6-amino-1,2-benzopyrone
Shock

Keywords

  • cyclooxygenase
  • endotoxin
  • MAP kinase
  • nitric oxide
  • nuclear factor xB
  • prostaglandins
  • septic shock
  • superoxide
  • tumor necrosis factor

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

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. / Szabo, Csaba; Wong, H. R.; Bauer, P. I.; Kirsten, E.; O'Connor, M.; Zingarelli, B.; Mendeleyev, J.; Hasko, G.; Vizi, E. S.; Salzman, A. L.; Kun, E.

In: International Journal of Oncology, Vol. 10, No. 6, 1997, p. 1093-1101.

Research output: Contribution to journalArticle

Szabo, C, Wong, HR, Bauer, PI, Kirsten, E, O'Connor, M, Zingarelli, B, Mendeleyev, J, Hasko, G, Vizi, ES, Salzman, AL & Kun, E 1997, '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', International Journal of Oncology, vol. 10, no. 6, pp. 1093-1101.
Szabo, Csaba ; Wong, H. R. ; Bauer, P. I. ; Kirsten, E. ; O'Connor, M. ; Zingarelli, B. ; Mendeleyev, J. ; Hasko, G. ; Vizi, E. S. ; Salzman, A. L. ; Kun, E. / 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. In: International Journal of Oncology. 1997 ; Vol. 10, No. 6. pp. 1093-1101.
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T1 - 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

AU - Szabo, Csaba

AU - Wong, H. R.

AU - Bauer, P. I.

AU - Kirsten, E.

AU - O'Connor, M.

AU - Zingarelli, B.

AU - Mendeleyev, J.

AU - Hasko, G.

AU - Vizi, E. S.

AU - Salzman, A. L.

AU - Kun, E.

PY - 1997

Y1 - 1997

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KW - septic shock

KW - superoxide

KW - tumor necrosis factor

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