PHOSPHATIDYL SERINE IS INVOLVED IN THE REDUCED RATE OF TRANSCRIPTION OF THE INDUCIBLE NITRIC-OXIDE SYNTHASE GENE IN MACROPHAGES FROM TUMOR-BEARING MICE

Upon stimulation with LPS, peritoneal-elicited macrophages (PEM) from mammary tumor-bearing mice display a diminished ability to produce nit ric oxide (NO) and lyse tumor targets, in contrast, when these cells a re stimulated with LPS in combination with IFN-gamma, they perform the se functions at normal levels. Kinetic studies revealed that these def ects became more pronounced with tumor progression and were accompanie d by similar changes in inducible nitric oxide synthase (iNOS) mRNA le vels, Since this tumor is known to produce PGE(2), granulocyte-macroph age CSF (CM-CSF), and phosphatidyl serine, we evaluated the effects of these products on NO production and cytolytic activity, Pretreatment of normal PEM with PGE(2) or recombinant GM-CSF had negligible effects on NO production and cytolytic capacity. In contrast, phosphatidyl se rine caused a concentration-dependent inhibition of these functions in response to LPS, which could be partially overcome by the addition of IFN-gamma. Moreover, iNOS mRNA levels paralleled these changes and we re analogous to the alterations observed in the tumor-bearers' PEM. iN OS mRNA stability was not reduced in these cells; however, the rate of transcription was diminished relative to normal levels, suggesting th at the defects causing these alterations are occurring at or before th e level of iNOS transcription. These data implicate tumor-derived phos phatidyl serine in the alterations observed in tumor-bearers' macropha ges and suggest that reduced iNOS transcription is responsible for the diminished capacity of these macrophages to produce NO and lyse tumor targets.