Effect of the phosphodiesterase III inhibitor amrinone on cytokine and nitric oxide production in immunostimulated J774.1 macrophages

Zoltán H. Németh, Csaba Szabo, György Haskó, Andrew L. Salzman, E. Sylvester Vizi

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

The level of intracellular cyclic nucleotides is a regulatory factor in a variety of immune processes. Increases in intracellular cyclic AMP (cAMP) and/or cyclic GMP (cGMP) concentration by the inhibition of phosphodiesterase have been shown to modulate the inflammatory response. Amrinone is a clinically used positive inotropic agent which elevates intracellular cAMP and cGMP levels by selective inhibition of the phosphodiesterase III isoenzyme. In the current study, we investigated the effect of various concentrations (1-300 μM) of amrinone on lipopolysaccharide-induced production of pro- and anti-inflammatory cytokines and of nitric oxide (NO) in vitro. In cultured murine J774.1 macrophages, 1 ng/ml-l0 μg/ml of lipopolysaccharide from Escherichia coli O55:B5 induced production of tumor necrosis facter-α (TNF-α), interleukin-10, and nitrite (breakdown product of NO). Pretreatment of cells with amrinone caused a dose-dependent suppression of TNF-α production in the concentration range of 1-100 μM. Furthermore, this drug suppressed NO production in the range of 30-300 μM. Similarly to the results in the J774.1 cells, amrinone also inhibited TNF-α and NO production in the range of 10-100 μM in primary rat peritoneal macrophages. At 300 μM, but not at lower concentrations, amrinone inhibited interleukin-10 production in lipopolysaccharide-treated J774.1 macrophages. Pretreatment of the macrophages with 100 and 300 μM amrinone increased the lipopolysaccharide-elicited translocation of nuclear factor-κB. Taken together, our results indicate that the phosphodiesterase III inhibitor amrinone modulates the activation/production of many pro- and anti-inflammatory factors in endotoxin-stimulated cells. It remains to be further investigated how such immunomodulatory effects contribute to the clinical profile of the agent.

Original languageEnglish (US)
Pages (from-to)215-221
Number of pages7
JournalEuropean Journal of Pharmacology
Volume339
Issue number2-3
DOIs
StatePublished - Nov 27 1997
Externally publishedYes

Fingerprint

Amrinone
Type 3 Cyclic Nucleotide Phosphodiesterases
Phosphodiesterase Inhibitors
Nitric Oxide
Macrophages
Cytokines
Lipopolysaccharides
Necrosis
Cyclic GMP
Cyclic AMP
Interleukin-10
Anti-Inflammatory Agents
Neoplasms
Cyclic Nucleotides
Phosphoric Diester Hydrolases
Peritoneal Macrophages
Nitrites
Endotoxins
Isoenzymes
Escherichia coli

Keywords

  • cAMP
  • cGMP
  • Interleukin-10
  • Lipopolysaccharide
  • Macrophage
  • Monocyte
  • Nitric oxide (NO)
  • Phosphodiesterase III inhibitor
  • TNF-α (tumor necrosis factor-α)

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Pharmacology

Cite this

Effect of the phosphodiesterase III inhibitor amrinone on cytokine and nitric oxide production in immunostimulated J774.1 macrophages. / Németh, Zoltán H.; Szabo, Csaba; Haskó, György; Salzman, Andrew L.; Vizi, E. Sylvester.

In: European Journal of Pharmacology, Vol. 339, No. 2-3, 27.11.1997, p. 215-221.

Research output: Contribution to journalArticle

Németh, Zoltán H. ; Szabo, Csaba ; Haskó, György ; Salzman, Andrew L. ; Vizi, E. Sylvester. / Effect of the phosphodiesterase III inhibitor amrinone on cytokine and nitric oxide production in immunostimulated J774.1 macrophages. In: European Journal of Pharmacology. 1997 ; Vol. 339, No. 2-3. pp. 215-221.
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AU - Vizi, E. Sylvester

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