The main goal of this research is to access how select fatty acids modulate mononuclear phagocyte function with particular reference to tumoricidal activity. We, as well as others, have shown that diets high in marine fish oils, like menhaden fish oil (MFO) have a differential influence on macrophage function as compared to diets high in vegetable oils, such as safflower oil (SAF). Our findings indicate that manipulation of dietary fatty acids can alter macrophage activation in a manner both dependent and independent of altered eicosanoid synthesis. This change may effect both afferent and efferent pathways of tumoricidal activation. Afferent pathways would involve processing of signals including signal transduction whereas efferent functions would involve execution of a specific response. Consequently we propose initially to assess how dietary fat influences an afferent hyporesponsive to interferon-gamma (IFNgamma) as compared to SAF macrophages. First, we will determine how dietary n-3 fats modulate select events in signal transduction; thus, experiments will assess IFNgamma receptor number and affinity, early events in signal transduction, alteration of protein kinase C, and transcription of select genes associated with activation. Second, we will focus on how dietary fat differentially influences macrophage efferent activity, specifically, select mediators of cytolysis.
The third aim i s to determine the mechanisms by which dietary fat can modulate LPS-induced TNFalpha production. For that, the nature and location of production as well as rate of transcript degradation will be assessed. Our previous findings indicate a difference between macrophages from mice fed n-3 and n-6 fatty acids with respect to the kinetics of TNFalpha by LPS-activated macrophages from mice fed n-3 fatty acid diets.
This aim will then focus on production, location, and receptors for TNFalpha as well as involvement of PGE2 in clearance. Finally we will assess how lipoxygenase metabolites can modulate macrophage tumoricidal activity. Previously, we have defined some of the ways in which dietary n-3 and n-6 fatty acids influence macrophage function. Now we wish to determine some of the possible mechanisms by which that occurs. An understanding of how dietary fats influence macrophage afferent and efferent function may help to elucidate the role dietary fats play in tumorigenesis.
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