Fatty acids and immune responses - A new perspective in searching for clues to mechanism

Dietary essential fatty acids are the precursors for eicosanoids. Among the eicosanoids derived from arachidonic acid, prostaglandin (PG) E-2 is known to possess immunosuppressive actions. Thus, it has been a prevailing hypot hesis that the immuno-modulatory roles of dietary fatty acids are mediated at least in part through the alteration of PG biosynthesis. PGs exert their biological effects through their cognate receptors. There are four subtype s of PGE receptors (EP1, EP2, EP3, and EP4) so far identified. Although the association of EP receptors with G proteins coupled to adenylate cyclase a nd the mobilization of intracellular calcium are well documented, downstrea m signaling pathways for these receptors are virtually unknown. Identificat ion of downstream signaling pathways for each subtype of EP receptors and t arget genes regulated by the activation of the receptor will help with our understanding of the mechanism by which dietary fatty acids affect immune r esponses through the modulation of PGE(2) biosynthesis. Emerging evidence s uggests that fatty acids can additionally act as second messengers, regulat ors of signal transducing molecules or transcription factors. Acylation wit h long-chain fatty acids can occur on a variety of signaling molecules and can affect their membrane translocation and functions. Dietary fatty acids can alter functional properties of lipid mediators by changing the composit ion of acyl moieties of these molecules. Evidence accumulated recently indi cates that long-chain unsaturated fatty acids and their metabolites bind an d activate peroxisome proliferator-activated receptors (PPARs). PPARs are n uclear hormone receptors and transcription factors that regulate the expres sion of broad arrays of genes involved not only in lipid and glucose metabo lism, but also in immune and inflammatory responses. PPARs may therefore be important cellular targets that mediate modulation of immune responses by dietary fatty acids. Together, it becomes clear now that multiple steps in various receptor-mediated signaling pathways can be modulated by dietary fa tty acids. It will be a challenging task to quantitatively determine how di fferent fatty acids alter functional properties of multitude of signaling c omponents and final cellular responses. Elucidating the mechanism of action s of fatty acids on receptor-mediated signaling pathways in immune-competen t cells will provide a new insight for understanding the immuno-modulatory roles of dietary fatty acids.