What makes eicosanoids

Eicosanoids derived from omega 6 fatty acids tend to be pro-inflammatory while those derived from omega 3 fatty acids tend to be anti-inflammatory or perhaps more accurately, less active. Eicosanoids are also related to docosanoids , signaling molecules derived primarily from docosahexaenoic acid DHA and resolvins and lipoxins , signaling molecules that induce the resolution of inflammation following acute infection or injury that are made from EPA and EHA.

The majority of eicosanoids require arachidonic acid , which is cleaved from cell membranes by phospholipase A2 PLA2 enzymes. Most cells produce insignificant amount of eicosanoids under normal conditions and produce a small number of specific eicosanoids when exposed to stimuli that activate PLA2.

Eicosanoids are involved in vasodilation and vasoconstriction, promotion of sleep, pain and fever. They pay a role in up- or down-regulating inflammatory cytokines. What eicosanoids cells produce and their effects depend on the type of cell, the tissue in which that cell is found, and the cell's activation state.

For example, those produced via the COX enzyme pathway generate the symptoms commonly associated with inflammation: heat, swelling, redness, and pain. There is some debate about the role of PGE 2 in the differentiation and expansion of Th17 cells Sakata et al. In Treg differentiation the majority of reports seem to suggest an enhancing effect Baratelli et al. Due to its role in promoting Treg differentiation and inhibiting effector T cell function and proliferation, PGE 2 has traditionally been considered an immunosuppressant, but with recent studies showing a possible enhancing effect of this eicosanoid on Th17 and Th1 differentiation, some have argued that the picture is more nuanced Sakata et al.

The first step in leukotriene biosynthesis, conversion of arachidonic acid to the unstable epoxide intermediate LTA 4 , is catalyzed by 5-LOX, an enzyme shown to occur in human T cell lines as well as in purified peripheral blood T cells Cook-Moreau et al.

However, some have noted that T lymphocytes require exogenous arachidonic acid in order to synthesize leukotrienes Cook-Moreau et al. This is interesting in light of the proposed transcellular eicosanoid biosynthesis mechanism, and it has also been shown that LTA 4 can act as the transferred intermediate metabolite in some systems Folco and Murphy, ; Sala et al.

The BLT 2 receptor is more ubiquitously expressed across tissues, with very high expression levels in the spleen Yokomizo et al. In T cells, LTB 4 is primarily known for its role in chemotaxis, but it has also been shown to have other functions, for instance in differentiation and proliferation. In addition, signaling through BLT 1 appears to enable adhesion of T cells to epithelial cells Tager et al.

In T cell differentiation, LTB 4 has been shown to promote Th17 and inhibit Treg generation, which may be of relevance in autoimmune diseases such as rheumatoid arthritis Chen et al. However, it should be noted that early reports from had suggested that LTB 4 may have an immunoregulatory role by inducing so-called suppressor T cells Yamaoka and Kolb, ; Morita et al. Proliferation and cytokine production in T cells can also be affected by LTB 4. Recently, further receptors involved in cysteinyl leukotriene signaling have been identified, in particular GPR17, which is a ligand-independent negative regulator of CysLT 1 , as well as the LTE 4 -specific P2Y 12 Austen et al.

While it is unclear whether these latter two receptors are expressed in T cells, the CysLT 1 and CysLT 2 receptors have been shown to be expressed in a small fraction of peripheral blood T cells Figueroa et al. It also appears that expression of this receptor is significantly higher in resting Th2 cells than in Th1 cells or activated Th2 cells Parmentier et al.

Interestingly, both receptors can also be upregulated in response to inflammatory stimuli. Presumably, this upregulation has the effect of making T cells more responsive to cysteinyl leukotriene signaling in inflammatory environments. There is some functional evidence for a role of cysteinyl leukotriene signaling in T cells. For one, these molecules appear to be important in Th2 cells where, as mentioned above, the CysLT 1 receptor is present in significant amounts.

Further roles in Th2 cells include a demonstrated effect of LTD 4 on the induction of calcium signaling as well as chemotaxis in these cells, both processes being CysLT 1 -specific Parmentier et al.

Cysteinyl leukotriene signaling in Th2 cells may also be involved in disease. For instance, it has been suggested that cysteinyl leukotrienes may enhance GM-CSF stimulated Th2 functions in atopic asthmatic patients in vivo Faith et al. There has also been a suggested role for the cysteinyl leukotrienes in T cell-mediated late airway responses to allergen challenge, since treatment with the CysLT 1 antagonist pranlukast inhibits these responses Hojo et al.

Eicosanoids are an important class of lipid signaling mediators and have long been studied for their proinflammatory functions. In recent years, however, it has become evident that these molecules not only promote inflammation, but can occasionally also act as anti-inflammatory agents and have more complex and nuanced roles in the regulation of immune and inflammatory responses. Here, we have summarized the evidence for the expression of and signaling by some important eicosanoids, the AA-derived prostanoids and the leukotrienes, in T lymphocytes.

These lipid mediators regulate a number of functions in T cells, including proliferation, apoptosis, cytokine secretion, differentiation, chemotaxis, and more. Through these processes, eicosanoids regulate a wide array of physiological processes, ranging from inflammatory processes such as asthma and allergies, to immune regulation and involvement in graft rejection, as well as diseases such as cancer and AIDS.

There is significant interest in targeting some of these pathways for therapeutic gain and it is therefore crucial to develop a complete understanding of all the different physiological functions of these important signaling mediators. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Indeed, there are suggestions that arachidonic acid per se may have some biological importance in animal tissues; for example, the cellular level of unesterified arachidonic acid may be a mechanism by which apoptosis is regulated.

It is reported to be a safe protective agent against blood flukes of the genus Schistosoma by activating the tegument-associated neutral sphingomyelinase of the parasites to disrupt the membrane. The oxygenated metabolites derived from arachidonic and related fatty acids are produced through a series of complex interrelated biosynthetic pathways sometimes termed the 'arachidonate or eicosanoid cascade '. The structures of some examples of the important eicosanoid classes are illustrated below.

The prostanoids prostaglandins, thromboxanes and prostacyclins have distinctive ring structures in the centre of the molecule. While the hydroxyeicosatetraenes are apparently simpler in structure, they are precursors for families of more complex molecules, such as the leukotrienes and lipoxins. The 'natural' eicosanoids are produced enzymatically with great stereochemical precision, and this is essential for their biological functions.

They are highly potent in the nanomolar range in vitro in the innumerable activities that have been defined, especially in relation to inflammatory responses, pain and fever. Most organs and cell types produce them, but with a high degree of tissue specificity, and some are even synthesised cooperatively between cells. Biosynthesis of eicosanoids involves the action of multiple enzymes, several of which can be rate limiting, not least the selective mechanisms for incorporation of arachidonate into phospholipids, including the formation of specific coA esters and remodelling by the Lands cycle.

The figure below summarizes in simplistic terms the various pathways for the subsequent formation of eicosanoids from phospholipid precursors. The first step in their biosynthesis is the production of free arachidonic acid in tissues from membrane phospholipids upon stimulation of the enzyme phospholipase A 2 by various physiological and pathological factors, including hormones and cytokines.

There are then three main enzymatic pathways for eicosanoid formation, involving cyclooxygenases COXs , lipoxygenases LOXs and epoxygenases of the cytochrome P family CYPs ; the last are also important for sterol and bile acid oxidation. There are several lipoxygenases that act upon different positions of arachidonic acid, mainly 5, 12 and 15, although an 8-lipoxygenase is also relevant, to produce various hydroperoxyeicosatetraenoic acids HPETEs and thence into hydroxyeicosatetraenoic acids HETEs and further products.

While many of the requisite enzymes, precursors and products are specific to particular types of cells, the close proximity of some cell types can facilitate the transfer of eicosanoids between cells for further metabolism, and for example some of the leukotrienes are produced by trans-cellular mechanisms. Most cell types can produce eicosanoids from phospholipid-derived precursors in this way, although much research has been concerned with those cells that are part of the innate immune system.

In addition, triacylglycerols in cytoplasmic lipid droplets of human mast cells, which are potent mediators of immune reactions and influence many inflammatory diseases, have a high content of arachidonic acid, which can be released by adipose triacylglycerol lipase as a substrate for production of specific eicosanoids when the cells are stimulated appropriately.

Indeed, there are now suggestions that lipid droplets in all cell types are essential for the response mechanisms to cellular stress, including inflammation and immunity, and act as hubs to integrate metabolic and inflammatory processes.

Via their lipolytic machinery, they regulate the availability of fatty acids for the activation of signalling pathways and for the production of oxylipins from polyunsaturated fatty acids.

Eicosanoids are generated mainly from unesterified fatty acids, not the CoA esters, and they function in this form, but it is increasingly recognized that they may occur and some may indeed be synthesised while esterified to other lipids. These may simply be an inert storage form available for when a rapid response is required, but some also be active biologically as esters. This is especially true for oxygenated forms of endocannabinoids.

Ultimately, many of the eicosanoids produced in this way are directed to the cellular membranes where they can interact with specific receptors. While the eicosanoids were the first to be identified and studied intensively and I have used them as the main examples in this web page for illustrative purposes, it is now recognized that docosanoids protectins, resolvins and maresins or 'specialized pro-resolving mediators' or SPMs derived from the n -3 family of fatty acids such as EPA and DHA may be just as important in their biological functions, often opposing the actions of the eicosanoids.

Octadecanoids derived from linoleate also have vital biological properties. All of these are oxylipins are produced by related means, often using the same enzymes as in eicosanoid production, so they are important elements of this story.

Jasmonic acid, for example, contains a cyclopentanone ring analogous to that in some prostaglandins, and the jasmonates have important signalling functions in relation to plant development and defense against pathogens and abiotic stresses of various kinds. Plants do not have the COX enzymes, but they do have lipoxygenases, which in fact were first characterized from plants, and a variety of other oxidases.

Arachidonic acid has only rarely been encountered in higher plants, but it is a constituent of some algae, fungi and moulds. During fungal infections of plants, it is known to elicit the production of plant defence compounds phytoalexins , probably after conversion to oxygenated metabolites. Fungal species that are pathogenic to animals such as Aspergillus , Candida , and Cryptococcus spp.

Autoxidation: In contrast to the enzymatic reactions, lipids can be oxidized non-enzymatically in all animal and plant tissues in an uncontrolled manner by free radical mechanisms that involve an initial attack by free radicals, followed by chain propagation and ultimately termination steps.

Such reactions occur on intact lipids and the result is usually a complex mixture of positional and stereo isomers of hydroperoxides that can rapidly rearrange or react to form other products that may also have biological activity both in the lipid-bound and free state. Among these are the oxidized phospholipids , isoprostanes and secondary oxygenated metabolites, often with reactive electrophilic carbonyl groups, such as short-chain aldehydes.

Most of the arachidonic acid and other polyunsaturated fatty acids in animal tissues is in esterified form, mainly in phospholipids and in phosphatidylinositol and the polyphosphoinositides in particular. Before this arachidonate can be used for eicosanoid synthesis, it must be released by the action of the enzyme phospholipase A 2 by the hydrolysis of the ester bond at the sn -2 position of membrane phospholipids, which are usually enriched in this acid; the other products are lysophospholipids.

In addition to phosphatidylinositol, phosphatidylcholine and phosphatidylethanolamine can be substrates for arachidonic acid release, depending on the tissue and physiological conditions. This reaction sets in motion a cascade of cellular processes that involve cyclooxygenases, lipoxygenases and cytochrome P oxidases, which are key enzymes in the biosynthesis of oxylipins of all kinds.

They are all water-soluble, membrane-associated enzymes with distinct structures and biological functions, and each has a characteristic active site, where the substrate binds, and an interfacial surface that facilitates association with cellular membranes. In general, different isoforms of these and other phospholipase As are present in specific tissues, cell types or organelles, where they each have particular substrate specificities and functions.

Indeed, it is believed to be rate limiting for eicosanoid production in many tissues. In addition to control via transcriptional regulation, the activity of the enzyme is responsive to various stimuli, such as hormones, cytokines and neurotransmitters.

In particular, it has been demonstrated that ceramidephosphate and phosphatidylinositol 4,5-bisphosphate bind to the enzyme. The latter is bound in a stoichiometry and is required for activation and translocation of the enzyme to the site of action.