Role of 5′-lipoxygenase metabolites in the activation of peritoneal macrophages for tumoricidal function

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Abstract

Metabolites of arachidonic acid have been shown to be potent biological modulators of macrophage function. While the role of cyclooxygenase metabolites of arachidonic acid have been well studied, metabolites of lipoxygenase have not. In this report, we evaluate the role that select 5′-lipoxygenase (5′-LO) products may play in macrophage activation for select tumoricidal functions. When thioglycollate-elicited macrophages were treated with inhibitors of 5′-LO during activation, cytolytic capacity, nitric oxide production, and tumor necrosis factor-α production were significantly inhibited. Moreover, both an inhibitor of the 5′-LO-activating protein and an inhibitor of glutathione-s-transferase (GST) significantly decreased macrophage tumoricidal function. The activating agents used were able to stimulate 5′-LO activity which was measured by quantitating secreted LTC4. Increased production of PGE2 by shunting could have been the cause for decreased macrophage tumoricidal function. However, treatment of macrophages with inhibitors of 5′-LO during lipopolysaccharide stimulation did not increase formation of PGE2. When select 5′-LO metabolites were added to cultures during activation and 5′-LO inhibition, tumoricidal activity could not be restored, even when the metabolites were encapsulated in liposomes. These results suggest that the activity of 5′-LO and GST are important for macrophage activation. However, the specific role of 5′-LO metabolites has not been completely established.

Original languageEnglish (US)
Pages (from-to)115-122
Number of pages8
JournalCellular Immunology
Volume160
Issue number1
DOIs
StatePublished - 1995

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Arachidonate 5-Lipoxygenase
Peritoneal Macrophages
Macrophages
Lipoxygenase Inhibitors
Macrophage Activation
Glutathione Transferase
Dinoprostone
5-Lipoxygenase-Activating Protein Inhibitors
Thioglycolates
Leukotriene C4
Lipoxygenase
Prostaglandin-Endoperoxide Synthases
Arachidonic Acid
Liposomes
Lipopolysaccharides
Nitric Oxide
Tumor Necrosis Factor-alpha

ASJC Scopus subject areas

  • Immunology
  • Cell Biology

Cite this

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title = "Role of 5′-lipoxygenase metabolites in the activation of peritoneal macrophages for tumoricidal function",
abstract = "Metabolites of arachidonic acid have been shown to be potent biological modulators of macrophage function. While the role of cyclooxygenase metabolites of arachidonic acid have been well studied, metabolites of lipoxygenase have not. In this report, we evaluate the role that select 5′-lipoxygenase (5′-LO) products may play in macrophage activation for select tumoricidal functions. When thioglycollate-elicited macrophages were treated with inhibitors of 5′-LO during activation, cytolytic capacity, nitric oxide production, and tumor necrosis factor-α production were significantly inhibited. Moreover, both an inhibitor of the 5′-LO-activating protein and an inhibitor of glutathione-s-transferase (GST) significantly decreased macrophage tumoricidal function. The activating agents used were able to stimulate 5′-LO activity which was measured by quantitating secreted LTC4. Increased production of PGE2 by shunting could have been the cause for decreased macrophage tumoricidal function. However, treatment of macrophages with inhibitors of 5′-LO during lipopolysaccharide stimulation did not increase formation of PGE2. When select 5′-LO metabolites were added to cultures during activation and 5′-LO inhibition, tumoricidal activity could not be restored, even when the metabolites were encapsulated in liposomes. These results suggest that the activity of 5′-LO and GST are important for macrophage activation. However, the specific role of 5′-LO metabolites has not been completely established.",
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AU - Hubbard, Neil

AU - Erickson, Kent L

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N2 - Metabolites of arachidonic acid have been shown to be potent biological modulators of macrophage function. While the role of cyclooxygenase metabolites of arachidonic acid have been well studied, metabolites of lipoxygenase have not. In this report, we evaluate the role that select 5′-lipoxygenase (5′-LO) products may play in macrophage activation for select tumoricidal functions. When thioglycollate-elicited macrophages were treated with inhibitors of 5′-LO during activation, cytolytic capacity, nitric oxide production, and tumor necrosis factor-α production were significantly inhibited. Moreover, both an inhibitor of the 5′-LO-activating protein and an inhibitor of glutathione-s-transferase (GST) significantly decreased macrophage tumoricidal function. The activating agents used were able to stimulate 5′-LO activity which was measured by quantitating secreted LTC4. Increased production of PGE2 by shunting could have been the cause for decreased macrophage tumoricidal function. However, treatment of macrophages with inhibitors of 5′-LO during lipopolysaccharide stimulation did not increase formation of PGE2. When select 5′-LO metabolites were added to cultures during activation and 5′-LO inhibition, tumoricidal activity could not be restored, even when the metabolites were encapsulated in liposomes. These results suggest that the activity of 5′-LO and GST are important for macrophage activation. However, the specific role of 5′-LO metabolites has not been completely established.

AB - Metabolites of arachidonic acid have been shown to be potent biological modulators of macrophage function. While the role of cyclooxygenase metabolites of arachidonic acid have been well studied, metabolites of lipoxygenase have not. In this report, we evaluate the role that select 5′-lipoxygenase (5′-LO) products may play in macrophage activation for select tumoricidal functions. When thioglycollate-elicited macrophages were treated with inhibitors of 5′-LO during activation, cytolytic capacity, nitric oxide production, and tumor necrosis factor-α production were significantly inhibited. Moreover, both an inhibitor of the 5′-LO-activating protein and an inhibitor of glutathione-s-transferase (GST) significantly decreased macrophage tumoricidal function. The activating agents used were able to stimulate 5′-LO activity which was measured by quantitating secreted LTC4. Increased production of PGE2 by shunting could have been the cause for decreased macrophage tumoricidal function. However, treatment of macrophages with inhibitors of 5′-LO during lipopolysaccharide stimulation did not increase formation of PGE2. When select 5′-LO metabolites were added to cultures during activation and 5′-LO inhibition, tumoricidal activity could not be restored, even when the metabolites were encapsulated in liposomes. These results suggest that the activity of 5′-LO and GST are important for macrophage activation. However, the specific role of 5′-LO metabolites has not been completely established.

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