Phosphatidyl Serine Is Involved in the Reduced Rate of Transcription of the Inducible Nitric Oxide Synthase Gene in Macrophages from Tumor-Bearing Mice

Michael R. DiNapoli, Cesar L. Calderon, Diana M Lopez

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Abstract

Upon stimulation with LPS, peritoneal-elicited macrophages (PEM) from mammary tumor-bearing mice display a diminished ability to produce nitric oxide (NO) and lyse tumor targets. In contrast, when these cells are stimulated with LPS in combination with IFN-γ, they perform these functions at normal levels. Kinetic studies revealed that these defects became more pronounced with tumor progression and were accompanied by similar changes in inducible nitric oxide synthase (iNOS) mRNA levels. Since this tumor is known to produce PGE2, granulocyte-macrophage CSF (GM-CSF), and phosphatidyl serine, we evaluated the effects of these products on NO production and cytolytic activity. Pretreatment of normal PEM with PGE2 or recombinant GM-CSF had negligible effects on NO production and cytolytic capacity. In contrast, phosphatidyl serine caused a concentration-dependent inhibition of these functions in response to LPS, which could be partially overcome by the addition of IFN-γ. Moreover, iNOS mRNA levels paralleled these changes and were analogous to the alterations observed in the tumor-bearers' PEM. iNOS mRNA stability was not reduced in these cells; however, the rate of transcription was diminished relative to normal levels, suggesting that the defects causing these alterations are occurring at or before the level of iNOS transcription. These data implicate tumor-derived phosphatidyl serine in the alterations observed in tumor-bearers' macrophages and suggest that reduced iNOS transcription is responsible for the diminished capacity of these macrophages to produce NO and lyse tumor targets.

Original languageEnglish
Pages (from-to)1810-1817
Number of pages8
JournalJournal of Immunology
Volume158
Issue number4
StatePublished - Feb 15 1997

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Phosphatidylserines
Nitric Oxide Synthase Type II
Macrophages
Nitric Oxide
Peritoneal Macrophages
Genes
Neoplasms
Dinoprostone
Granulocytes
Messenger RNA
RNA Stability
Breast Neoplasms

ASJC Scopus subject areas

  • Immunology

Cite this

Phosphatidyl Serine Is Involved in the Reduced Rate of Transcription of the Inducible Nitric Oxide Synthase Gene in Macrophages from Tumor-Bearing Mice. / DiNapoli, Michael R.; Calderon, Cesar L.; Lopez, Diana M.

In: Journal of Immunology, Vol. 158, No. 4, 15.02.1997, p. 1810-1817.

Research output: Contribution to journalArticle

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abstract = "Upon stimulation with LPS, peritoneal-elicited macrophages (PEM) from mammary tumor-bearing mice display a diminished ability to produce nitric oxide (NO) and lyse tumor targets. In contrast, when these cells are stimulated with LPS in combination with IFN-γ, they perform these functions at normal levels. Kinetic studies revealed that these defects became more pronounced with tumor progression and were accompanied by similar changes in inducible nitric oxide synthase (iNOS) mRNA levels. Since this tumor is known to produce PGE2, granulocyte-macrophage CSF (GM-CSF), and phosphatidyl serine, we evaluated the effects of these products on NO production and cytolytic activity. Pretreatment of normal PEM with PGE2 or recombinant GM-CSF had negligible effects on NO production and cytolytic capacity. In contrast, phosphatidyl serine caused a concentration-dependent inhibition of these functions in response to LPS, which could be partially overcome by the addition of IFN-γ. Moreover, iNOS mRNA levels paralleled these changes and were analogous to the alterations observed in the tumor-bearers' PEM. iNOS mRNA stability was not reduced in these cells; however, the rate of transcription was diminished relative to normal levels, suggesting that the defects causing these alterations are occurring at or before the level of iNOS transcription. These data implicate tumor-derived phosphatidyl serine in the alterations observed in tumor-bearers' macrophages and suggest that reduced iNOS transcription is responsible for the diminished capacity of these macrophages to produce NO and lyse tumor targets.",
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