Modulation of lipid derived mediators by polyunsaturated fatty acids

Abstract

Cell stimulation by a number of agonists triggers the formation of products of lipid hydrolysis, which act either as intracellular mediators of signal transduction or as modulators of cell-cell interactions. This process is mediated by the activation of hydrolytic enzymes, the phospholipases (PLase), especially the A 2 and C, acting on cell phospholipids (PL). Among the major products being formed, the following: a) the inositol phosphates (IP), especially IP 3, and diacylglycerols (DAG) generated intracellularly from phosphoinositides through PLase C, b) the eicosanoids, the arachidonic acid (AA) metabolites produced through combined PLase A 2 and (cyclo- and lip-) oxygenase activities, and released from cells, c) the ether lipid PAF, derived from alkylacyl phosphatidylcholine through PLase A 2, have attracted the attention of investigators for their important biological roles. Interest has also been recently developed towards products of sphingolipid hydrolysis, sphingosine and ceramide, which are generated by various cell types after stimulation, and exert biological activities. Cell glycerophospholipids are rich in long-chain polyunsaturated fatty acids (PUFA) of the n-6, namely AA 20:4 n-6, and n-3, mainly docosahexaenoic acid (DHA) 22:6, series. These compounds are differentially distributed among the various PL classes and their levels in cells are modulated through the intake with the diet of either the 18-C fatty acids (FA), precursors, linoleic 18:2 n-6, and, alpha-linolenic 18:3 n-3, respectively-followed by conversion to their long-chain PUFA derivatives, or through the intake of the preformed compounds. Levels of the long-chain PUFA in membranes can also be modulated in cultured cells, through manipulation of the supply with the growth medium. The incorporation of exogenous FA in cell lipids, in this type of study, however, follows patterns which are different from those observed in vivo after dietary manipulations. The levels of long chain n-6 and n-3 PUFA in cell phosphoglycerides modulate the generation of lipid derived mediators, in various types of cells, after in vitro stimulation. These effects can be ascribed to various mechanisms: 1. 1. Changes in eicosanoid production as a consequence of: a) changes in the levels of AA, the major precursor of these compounds, b) accumulation of long-chain PUFA of the n-3 series, which act as precursors (e.g. eicosapentaenoic acid (EPA), 20:5) of eicosanoids with biological activities different from those of the products derived from AA, or inhibitors (EPA) and/or modulators (DHA) of the AA oxygenases. 2. 2. Changes in the stimulated formation of other products of PL hydrolysis, such as the IP and PAF, possibly as a consequence of a modified micro-environment of the PLases, or as a consequence of modified eicosanoid production. The fomation of other mediators, such as the cytokines, in specialized cells, is also affected by changes of cell PUFA, possibly as an additional consequence of altered eicosanoid formation. In this presentation, examples of changes of cell n-6 and n-3 PUFA, obtained in circulating cells (e.g. platelets, leukocytes) through feeding studies in animals and humans, or induced in cultured cells after FA supplementation, will be presented and discussed, in relation to the effects on the production of eicosanoids and other lipid derived mediators.