Lipid bodies, lipid-rich cytoplasmic inclusions, are sites at which arachidonate-derived mediators of inflammation may form. Several findings indicate that lipid bodies have novel roles as specialized, inducible intracellular domains involved in eicosanoid formation by cells engaged in inflammatory reactions. First, lipid bodies are prominent in vivo within leukocytes associated with inflammation and likely to be engaged in stimulated eicosanoid formation. Second, lipid bodies contain esterified arachidonate. Third, specific enzymes pertinent to arachidonate metabolism, including MAP kinases, cytosolic phospholipase A2, cyclooxygenases, and lipoxygenases, are localized at lipid bodies. Fourth, lipid body formation is rapidly and specifically inducible in vitro and in vivo, by mechanisms involving the actions of several intracellular signaling pathways and requiring specific gene expression and de novo protein synthesis. Fifth, the capacity of leukocytes to form enhanced quantities of boty cyclooxygenase- and lipoxygenase-derived eicosanoids correlates with numbers of induced lipid bodies. Sixth, inhibitors of lipid body induction inhibit this enhanced eicosanoid production. Seventh, specific cytokines that affect lipid metabolism, including tumor necrosis factor-alpha(TNF-alpha, are localized in lipid bodies. Therefore, of pertinence to cells involved in inflammation, lipid bodies are distinct intracellular domains whose formation is rapidly inducible and correlated with an enhanced capacity for both prostaglandin and leukotriene generation. Investigations will use biochemical, ultrastructural, histochemical and molecular biological approaches to study lipid bodies, both in situ within cells and as isolated subcellular structures. Studies will investigate mechanisms by which: 1) arachidonate-rich lipid bodies form, 2) arachidonate from lipid bodies is utilized to form eicosanoid mediators, and 3) lipid body associated proteins, including the cytokine TNF-alpha, function at lipid bodies. The capacity of lipid body formation to be specifically and rapidly induced in leukocytes enhances eicosanoid mediator formation, and conversely pharmacologic inhibition of lipid body induction represents a potential novel and specific target for anti-inflammatory therapy. Understanding the functions of lipid bodies will elucidate mechanism, amenable to therapeutic inhibition, responsible for the heightened formation of eicosanoid mediators active in diverse immunologic, allergic an inflammatory reactions.
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