Melatonin and structurally similar compounds have differing effects on inflammation and mitochondrial function in endothelial cells under conditions mimicking sepsis

D A Lowes, A M Almawash, N R Webster, V L Reid, H F Galley

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Background Development of organ dysfunction associated with sepsis is due in part to oxidative damage to mitochondria. Melatonin regulates the sleep–wake cycle and also has potent antioxidant activity. The aim of this study was to determine the effects of melatonin and other structurally related compounds on mitochondrial function, endogenous glutathione (GSH), and control of cytokine expression under conditions mimicking sepsis.

Methods Human endothelial cells were treated with lipopolysaccharide (LPS) plus peptidoglycan G (PepG) to simulate sepsis, in the presence of melatonin, 6-hydroxymelatonin, tryptamine, or indole-3-carboxylic acid. Nuclear factor ¿B (NF¿B) activation, interleukin (IL)-6 and IL-8, total glutathione, mitochondrial membrane potential, and metabolic activity were measured.

Results LPS and PepG treatment resulted in elevated IL-6 and IL-8 levels preceded by activation of NF¿B (all P<0.0001). Treatment with all four compounds resulted in lower IL-6 and IL-8 levels, and lower NF¿B activation (P<0.0001). Loss of mitochondrial membrane potential and endogenous glutathione was seen when cells were exposed to LPS/PepG, but these were maintained in cells co-treated with melatonin, tryptamine, or 6-hydroxymelatonin (P<0.05), but not indole-3-carboxylic acid. Metabolic activity decreased after exposure to LPS/PepG and was maintained by melatonin and 6-hydroxymelatonin at the highest concentrations only.

Conclusions We have shown that in addition to melatonin, other structurally related indoleamine compounds have effects on NF¿B activation and cytokine expression, GSH, mitochondrial membrane potential, and metabolic activity in endothelial cells cultured under conditions mimicking sepsis. Further work is needed to determine whether these compounds represent therapeutic approaches for disrupting the oxidative stress-inflammatory response signalling pathway in sepsis.
Original languageEnglish
Pages (from-to)193-201
Number of pages9
JournalBritish Journal of Anaesthesia
Volume107
Issue number2
Early online date9 Jun 2011
DOIs
Publication statusPublished - Aug 2011

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Melatonin
Sepsis
Endothelial Cells
Peptidoglycan
Inflammation
Lipopolysaccharides
Mitochondrial Membrane Potential
Interleukin-8
Glutathione
Interleukin-6
Cytokines
Mitochondria
Oxidative Stress
Antioxidants
6-hydroxymelatonin

Keywords

  • antioxidants
  • cells, cultured
  • endothelium, vascular
  • glutathione
  • humans
  • inflammation
  • interleukin-6
  • interleukin-8
  • melatonin
  • membrane potential, mitochondrial
  • mitochondria
  • NF-kappa B
  • oxidative stress
  • sepsis
  • signal transduction

Cite this

Melatonin and structurally similar compounds have differing effects on inflammation and mitochondrial function in endothelial cells under conditions mimicking sepsis. / Lowes, D A; Almawash, A M; Webster, N R; Reid, V L; Galley, H F.

In: British Journal of Anaesthesia, Vol. 107, No. 2, 08.2011, p. 193-201.

Research output: Contribution to journalArticle

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abstract = "Background Development of organ dysfunction associated with sepsis is due in part to oxidative damage to mitochondria. Melatonin regulates the sleep–wake cycle and also has potent antioxidant activity. The aim of this study was to determine the effects of melatonin and other structurally related compounds on mitochondrial function, endogenous glutathione (GSH), and control of cytokine expression under conditions mimicking sepsis.Methods Human endothelial cells were treated with lipopolysaccharide (LPS) plus peptidoglycan G (PepG) to simulate sepsis, in the presence of melatonin, 6-hydroxymelatonin, tryptamine, or indole-3-carboxylic acid. Nuclear factor ¿B (NF¿B) activation, interleukin (IL)-6 and IL-8, total glutathione, mitochondrial membrane potential, and metabolic activity were measured.Results LPS and PepG treatment resulted in elevated IL-6 and IL-8 levels preceded by activation of NF¿B (all P<0.0001). Treatment with all four compounds resulted in lower IL-6 and IL-8 levels, and lower NF¿B activation (P<0.0001). Loss of mitochondrial membrane potential and endogenous glutathione was seen when cells were exposed to LPS/PepG, but these were maintained in cells co-treated with melatonin, tryptamine, or 6-hydroxymelatonin (P<0.05), but not indole-3-carboxylic acid. Metabolic activity decreased after exposure to LPS/PepG and was maintained by melatonin and 6-hydroxymelatonin at the highest concentrations only.Conclusions We have shown that in addition to melatonin, other structurally related indoleamine compounds have effects on NF¿B activation and cytokine expression, GSH, mitochondrial membrane potential, and metabolic activity in endothelial cells cultured under conditions mimicking sepsis. Further work is needed to determine whether these compounds represent therapeutic approaches for disrupting the oxidative stress-inflammatory response signalling pathway in sepsis.",
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TY - JOUR

T1 - Melatonin and structurally similar compounds have differing effects on inflammation and mitochondrial function in endothelial cells under conditions mimicking sepsis

AU - Lowes, D A

AU - Almawash, A M

AU - Webster, N R

AU - Reid, V L

AU - Galley, H F

PY - 2011/8

Y1 - 2011/8

N2 - Background Development of organ dysfunction associated with sepsis is due in part to oxidative damage to mitochondria. Melatonin regulates the sleep–wake cycle and also has potent antioxidant activity. The aim of this study was to determine the effects of melatonin and other structurally related compounds on mitochondrial function, endogenous glutathione (GSH), and control of cytokine expression under conditions mimicking sepsis.Methods Human endothelial cells were treated with lipopolysaccharide (LPS) plus peptidoglycan G (PepG) to simulate sepsis, in the presence of melatonin, 6-hydroxymelatonin, tryptamine, or indole-3-carboxylic acid. Nuclear factor ¿B (NF¿B) activation, interleukin (IL)-6 and IL-8, total glutathione, mitochondrial membrane potential, and metabolic activity were measured.Results LPS and PepG treatment resulted in elevated IL-6 and IL-8 levels preceded by activation of NF¿B (all P<0.0001). Treatment with all four compounds resulted in lower IL-6 and IL-8 levels, and lower NF¿B activation (P<0.0001). Loss of mitochondrial membrane potential and endogenous glutathione was seen when cells were exposed to LPS/PepG, but these were maintained in cells co-treated with melatonin, tryptamine, or 6-hydroxymelatonin (P<0.05), but not indole-3-carboxylic acid. Metabolic activity decreased after exposure to LPS/PepG and was maintained by melatonin and 6-hydroxymelatonin at the highest concentrations only.Conclusions We have shown that in addition to melatonin, other structurally related indoleamine compounds have effects on NF¿B activation and cytokine expression, GSH, mitochondrial membrane potential, and metabolic activity in endothelial cells cultured under conditions mimicking sepsis. Further work is needed to determine whether these compounds represent therapeutic approaches for disrupting the oxidative stress-inflammatory response signalling pathway in sepsis.

AB - Background Development of organ dysfunction associated with sepsis is due in part to oxidative damage to mitochondria. Melatonin regulates the sleep–wake cycle and also has potent antioxidant activity. The aim of this study was to determine the effects of melatonin and other structurally related compounds on mitochondrial function, endogenous glutathione (GSH), and control of cytokine expression under conditions mimicking sepsis.Methods Human endothelial cells were treated with lipopolysaccharide (LPS) plus peptidoglycan G (PepG) to simulate sepsis, in the presence of melatonin, 6-hydroxymelatonin, tryptamine, or indole-3-carboxylic acid. Nuclear factor ¿B (NF¿B) activation, interleukin (IL)-6 and IL-8, total glutathione, mitochondrial membrane potential, and metabolic activity were measured.Results LPS and PepG treatment resulted in elevated IL-6 and IL-8 levels preceded by activation of NF¿B (all P<0.0001). Treatment with all four compounds resulted in lower IL-6 and IL-8 levels, and lower NF¿B activation (P<0.0001). Loss of mitochondrial membrane potential and endogenous glutathione was seen when cells were exposed to LPS/PepG, but these were maintained in cells co-treated with melatonin, tryptamine, or 6-hydroxymelatonin (P<0.05), but not indole-3-carboxylic acid. Metabolic activity decreased after exposure to LPS/PepG and was maintained by melatonin and 6-hydroxymelatonin at the highest concentrations only.Conclusions We have shown that in addition to melatonin, other structurally related indoleamine compounds have effects on NF¿B activation and cytokine expression, GSH, mitochondrial membrane potential, and metabolic activity in endothelial cells cultured under conditions mimicking sepsis. Further work is needed to determine whether these compounds represent therapeutic approaches for disrupting the oxidative stress-inflammatory response signalling pathway in sepsis.

KW - antioxidants

KW - cells, cultured

KW - endothelium, vascular

KW - glutathione

KW - humans

KW - inflammation

KW - interleukin-6

KW - interleukin-8

KW - melatonin

KW - membrane potential, mitochondrial

KW - mitochondria

KW - NF-kappa B

KW - oxidative stress

KW - sepsis

KW - signal transduction

U2 - 10.1093/bja/aer149

DO - 10.1093/bja/aer149

M3 - Article

VL - 107

SP - 193

EP - 201

JO - British Journal of Anaesthesia

JF - British Journal of Anaesthesia

SN - 0007-0912

IS - 2

ER -