Pyrrolidine dithiocarbamate augments IL-10, inhibits TNF-α, MIP-1α, IL-12, and nitric oxide production and protects from the lethal effect of endotoxin

Zoltán H. Németh, G. Haskó, E. Vízi

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Abstract

During endotoxemia, immune cells activated by lipopolysaccharide (LPS) produce various inflammatory mediators, including cytokines and nitric oxide (NO). The genes of several mediators are activated in part by the rapid binding of the transcription factor nuclear factor-kappa B (NF-κB) to its promoter. The induction of this transcription factor can be blocked by a wide range of antioxidants, including pyrrolidine dithiocarbamate (PDTC). Here we investigated in mice the effect of this compound on the plasma tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin-1α (IL-1α), interleukin-6 (IL-6), interleukin-10 (IL-10), interleukin-12 (IL-12), macrophage inflammatory protein-1α (MIP-1α), and nitric oxide (NO) response to intraperitoneal (i.p.) injection of LPS. Pretreatment of animals with PDTC (10-100 mg/kg) 30 min prior to LPS challenge (4 mg/kg, i.p.) decreased plasma TNF-α, IL-12, MIP-1α, and nitrite/nitrate (breakdown products of NO) concentrations, but enhanced plasma levels of IL-10. Moreover, pretreatment of mice with PDTC (10-100 mg/kg, i.p.) did not alter LPS-induced (4 mg/kg) production of IL-1α, IL-6, and IFN-γ. Finally, PDTC (100 mg/kg) protected the mice against LPS (100 mg/kg)-induced lethality. These results indicate that blockade of the NF-κB pathway by PDTC has potent anti-inflammatory action in systemic inflammatory processes.

Original languageEnglish
Pages (from-to)49-53
Number of pages5
JournalShock
Volume10
Issue number1
Publication statusPublished - Jul 1998

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Macrophage Inflammatory Proteins
Interleukin-12
Endotoxins
Interleukin-10
Lipopolysaccharides
Nitric Oxide
Tumor Necrosis Factor-alpha
NF-kappa B
Interleukin-1
Interferons
Interleukin-6
Transcription Factors
Endotoxemia
Nitrites
Intraperitoneal Injections
Nitrates
Anti-Inflammatory Agents
Antioxidants
pyrrolidine dithiocarbamic acid
Cytokines

ASJC Scopus subject areas

  • Physiology
  • Critical Care and Intensive Care Medicine

Cite this

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title = "Pyrrolidine dithiocarbamate augments IL-10, inhibits TNF-α, MIP-1α, IL-12, and nitric oxide production and protects from the lethal effect of endotoxin",
abstract = "During endotoxemia, immune cells activated by lipopolysaccharide (LPS) produce various inflammatory mediators, including cytokines and nitric oxide (NO). The genes of several mediators are activated in part by the rapid binding of the transcription factor nuclear factor-kappa B (NF-κB) to its promoter. The induction of this transcription factor can be blocked by a wide range of antioxidants, including pyrrolidine dithiocarbamate (PDTC). Here we investigated in mice the effect of this compound on the plasma tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin-1α (IL-1α), interleukin-6 (IL-6), interleukin-10 (IL-10), interleukin-12 (IL-12), macrophage inflammatory protein-1α (MIP-1α), and nitric oxide (NO) response to intraperitoneal (i.p.) injection of LPS. Pretreatment of animals with PDTC (10-100 mg/kg) 30 min prior to LPS challenge (4 mg/kg, i.p.) decreased plasma TNF-α, IL-12, MIP-1α, and nitrite/nitrate (breakdown products of NO) concentrations, but enhanced plasma levels of IL-10. Moreover, pretreatment of mice with PDTC (10-100 mg/kg, i.p.) did not alter LPS-induced (4 mg/kg) production of IL-1α, IL-6, and IFN-γ. Finally, PDTC (100 mg/kg) protected the mice against LPS (100 mg/kg)-induced lethality. These results indicate that blockade of the NF-κB pathway by PDTC has potent anti-inflammatory action in systemic inflammatory processes.",
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T1 - Pyrrolidine dithiocarbamate augments IL-10, inhibits TNF-α, MIP-1α, IL-12, and nitric oxide production and protects from the lethal effect of endotoxin

AU - Németh, Zoltán H.

AU - Haskó, G.

AU - Vízi, E.

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N2 - During endotoxemia, immune cells activated by lipopolysaccharide (LPS) produce various inflammatory mediators, including cytokines and nitric oxide (NO). The genes of several mediators are activated in part by the rapid binding of the transcription factor nuclear factor-kappa B (NF-κB) to its promoter. The induction of this transcription factor can be blocked by a wide range of antioxidants, including pyrrolidine dithiocarbamate (PDTC). Here we investigated in mice the effect of this compound on the plasma tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin-1α (IL-1α), interleukin-6 (IL-6), interleukin-10 (IL-10), interleukin-12 (IL-12), macrophage inflammatory protein-1α (MIP-1α), and nitric oxide (NO) response to intraperitoneal (i.p.) injection of LPS. Pretreatment of animals with PDTC (10-100 mg/kg) 30 min prior to LPS challenge (4 mg/kg, i.p.) decreased plasma TNF-α, IL-12, MIP-1α, and nitrite/nitrate (breakdown products of NO) concentrations, but enhanced plasma levels of IL-10. Moreover, pretreatment of mice with PDTC (10-100 mg/kg, i.p.) did not alter LPS-induced (4 mg/kg) production of IL-1α, IL-6, and IFN-γ. Finally, PDTC (100 mg/kg) protected the mice against LPS (100 mg/kg)-induced lethality. These results indicate that blockade of the NF-κB pathway by PDTC has potent anti-inflammatory action in systemic inflammatory processes.

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