Eicosanoids effects

C. Mechanism of Action Most eicosanoid effects appear to be brought about by activation of cell surface receptors that are coupled by G proteins to adenylyl cyclase (producing cAMP) or the phosphatidylinositol cascade (producing IP3 and DAG second messengers). 

TNF activates inflammatory functions of various immune cells, not only as a direct effector but also as part of the cytokine network (synergism with IL-1, IFN-y, and LPS), as shown in Table 2 (K11). TNF interacts with the complement system and induces the additional release of eicosanoids. TNF has many effects on... 

A tritium isotope effect in high-performance liquid chromatography of 11 eicosanoids has been observed. Multi-tritium-labelled eicosanoids were eluted earlier than the corresponding unlabelled eicosanoid. Variations in retention time are 3-7%, depending on the separation conditions as well as on the number and position of the tritium substituents238. 

Dietary polyunsaturated fatty acids (PUFAs), especially the n-3 series that are found in marine fish oils, modulate a variety of normal and disease processes, and consequently affect human health. PUFAs are classified based on the position of double bonds in their lipid structure and include the n-3 and n-6 series. Dietary n-3 PUFAs include a-linolenic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) whereas the most common n-6 PUFAs are linoleic acid, y-linolenic acid, and arachidonic acid (AA). AA is the primary precursor of eicosanoids, which includes the prostaglandins, leukotrienes, and thromboxanes. Collectively, these AA-derived mediators can exert profound effects on immune and inflammatory processes. Mammals can neither synthesize n-3 and n-6 PUFAs nor convert one variety to the other as they do not possess the appropriate enzymes. PUFAs are required for membrane formation and function... 

A variety of biochemical and molecular mechanisms have been described to explain how PUFAs can modulate immune cell fate and function. The primary mechanism of action of dietary n-3 PUFAs involves the replacement of AA in the lipid membrane of the cells with either EPA or DHA. This, in effect, competitively inhibits the oxygenation of AA by the COX enzymes. For example, the EPA-induced suppression in the production of AA-derived eicosanoids is followed by a subsequent increase in the production of those from EPA. Generally, the EPA-derived eicosanoids are considered to be much less potent than those from AA, thus explaining, at least partially, the anti-inflammatory effects of PUFAs. A similar mechanism of action can be demonstrated for DHA, either directly or by retroconversion to EPA. 

In addition to its effects on haematopoietic cells, GM-CSF can also affect the function of mature cells. GM-CSF treatment increases the survival, cytotoxicity and eicosanoid formation by eosinophils, and can increase the tu-mouricidal activity, cytokine expression, surface antigen expression and oxidative metabolism of macrophages. It is chemotactic for endothelial cells, can induce the proliferation of some tumour cells, stimulates histamine release from basophils and affects the viability and function of Langerhans cells. Its effects on mature neutrophils are described in 7.2.1, 7.3.4. 

Adipocytes have an important secretory function. Numerous factors (collectively termed adipokines or adipocytokines), mostly peptides but also eicosanoids are produced by preadipocytes and mature adipocytes (Table 9.3). Some of these factors act in an autocrine or paracrine fashion to regulate adipogenesis, that is differentiation and maturation of adipocytes themselves, whilst others, notably, leptin, adiponectin and some cytokines act in truly endocrine way, having effects on the brain, endothelial cells, liver and skeletal muscle. Disturbance in secretion from adipocytes is associated with eating disorders and metabolic syndrome. 

Piccirillo et al. 1994). The effects of thromboxane A2 were examined in nondepressed, normai individuals. Thromboxane A2 was found to have direct CNS effects on hemodynamic, ACTH, and cortisol responses (Cudd 1998). Whether ginger has a significant effect on these processes and whether it has an antistress or antidepressant effect is speculative, but the eicosanoid activities of ginger and relationship to depression warrant further investigation. 

THC has been shown to aiter eicosanoid ieveis (Reichman et ai. 1987). Psychoactive, but not non psychoactive constituents aitered ieveis of prostagiandins (PGE and PGF). This effect was region-specific, aitering ieveis in the striatum but not cerebeiium. 

Srivastava KC. (1986). Isolation and effects of some ginger components of platelet aggregation and eicosanoid biosynthesis. Prostaglandins Leukot Med. 25(2-3) 187-98. 

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