Project: Research project

Project Details


Macrophages, as well as certain fatty acid derived eicosanoids,
have been shown to play an important role in inflammation,
immune response, and tumorigenesis. The production of
prostaglandin E2 by macrophages and its regulation of the
macrophage's ability to maintain a prolonged state of tumor
cytotoxicity has been described. However, other eicosanoids may
also regulate macrophage function. Therefore, the main goal of
this proposal is to assess how specific dietary fatty acid
precursors of prostaglandins of the 1,2, and 3 series and
lipoxygenase products of the 3,4, and 5 series modulate murine
mononuclear phagocyte function, with particular focus on
tumoricidal activation. For those studies, unique dietary oils with
high levels of linoleic, gamma-linolenic, or eicosapentanoic and
docosahexanoic acid, or low in linoleic acid will be fed. We
propose, first, to delineate the effects of selected dietary fatty
acids on macrophage functional activities. Specifically we will
assess the recruitment, development of functional and
differentiation markers, tumoricidal activation, and fatty acid
composition of murine peritoneal macrophages in mice fed
experimental diets. During that study modulation of the signals
required for macrophages to become fully cytolytic will be
determined. Because the dietary fats contain a mixture of fatty
acids, our second aim is to assess modulation of macrophage
tumoricidal capability when selected fatty acids, known to be
direct precursors of eicosanoids, are added to macrophages in
vitro. Because the major focus in the past has been on
arachidonic metabolites, we now propose to study the metabolism
and role of the other twenty carbon fatty acid precursors.
Several of those metabolites may have important anti-
inflammmatory characteristics. Thus, our third aim is to assess
which eicosanoids macrophages produce and which of those have
functional activity. For that, radiolabeled fatty acids will be
added and the eicosanoid products characterized by high-
performance liquid chromatography and confirmed by mass
spectrometry. Identified eicosanoids will be added back to
activated macrophages, either singly or as a mixture in a dose
response study to assess modulation of tumoricidal activity. The
information for these experiments should help to determine which
eicosanoids play an important role in modifying the ability of
macrophages to kill tumor cells and whether changing substrate
bioavailability through dietary sources will influence production
of those important eicosanoids. An understanding of eicosanoid
metabolism may help to elucidate the role dietary fat plays in
Effective start/end date6/1/8812/31/96


  • National Institutes of Health


  • Medicine(all)


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