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 tumorigenesis.
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