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Before describing how fatty acids are associated with inflammatory processes, I want to describe what the inflammation is and what the fatty acids are.
What is an inflammation?
Inflammation is an initial defense system that protects the host organism from infection. It initiates different processes such as pathogen killing and tissue repair to restore the homeostasis at the infected site. Typical examples of inflammation are redness, swelling, pain, loss of function and heating. In response to the inflammation, different chemical mediators are released such as cytokines, eicosanoids, chemokines and reactive oxygen species.
Inflammatory responses are self-regulative in nature that involve in the activation of negative feedback mechanisms. These negative feedback mechanisms are; secretion of anti-inflammatory cytokines, inhibition of pro-inflammatory signaling cascades, activation of regulatory cells, and blocking the receptors for the inflammatory mediators.
Fatty acids are the common dietary constituents that have some of the most important biological roles. They have metabolic, structural and functional roles in the body. Fatty acids are one of the important source of energy as well as the main components of the cell membrane. They are also the precursors of the signaling molecules.
Fatty acids can be saturated and unsaturated and length of the fatty acid can vary from 2-30 carbon or even more. Some of the important saturated fatty acids are octanoic acid (caprylic acid), decanoic acid (capric acid), dodecanoic acid (lauric acid), and hexacosanoic acid (palmitic acid) while some of the important unsaturated fatty acids are linoleic acid, α-linolenic acid, γ-linolenic acid, arachidonic acid, eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA).
Based on the distance of the first double bond from the methyl terminus, polyunsaturated fatty acids (PUFAs) are classified as omega-x (ω-x) where x determines the number of carbon atoms from the methyl terminus to the first double bond. There are two main classes of PUFAs; omega 3 or n-3 polyunsaturated fatty acids (such as α-linolenic) and omega 6 or n-6 polyunsaturated fatty acids (such as γ-linolenic acid).
Linoleic acid and α-linolenic acid are essential fatty acids because we can’t synthesize them in our body and must be taken through the diet. Though we can’t synthesize them but we can utilize them to synthesize other types of unsaturated fatty acids and inflammatory mediators. Metabolism of α-linolenic acid (ω-3 PUFA) will always give rise to other types of omega 3 fatty acids while metabolism of linoleic acid (ω-6 PUFA) will always give different types of omega 6 fatty acids.
PUFAs are important constituents of the membrane lipids such as phospholipids. However, the proportion of the omega 3 and omega 6 PUFAs may vary according to the dietary intake of the PUFAs. The α-linolenic acid can be obtained from green plant tissues while ω-6 PUFAs are abundant in vegetable oils. Other ω-3 PUFAs, such as EPA, DPA, and DHA are most abundant in fish.
Fatty acid-derived inflammatory mediators
Eicosanoids derived from arachidonic acid
Eicosanoids are the key metabolites that mediate and regulate the inflammatory processes. They are synthesized from arachidonic acid, a ω-6 polyunsaturated fatty acid (20C). There are different types of eicosanoids such as Prostaglandins (PGs), Leukotrienes (LTs), Thromboxanes and some other oxidized derivatives. Arachidonic acid is present in a higher concentration in the phospholipids of the inflammatory cell membranes where it constitutes the major precursor for the eicosanoid mediators.
It is now well established that animals fed with ω-6 arachidonic acid produce more prostaglandins while animals fed with omega 3 fatty acids such as eicosapentaenoic acid or docosahexaenoic acid produce lesser prostaglandins. However, eicosapentaenoic acid-derived eicosanoids have a different structure from the arachidonic acid-derived eicosanoids.
In addition to the differences in structure, eicosapentaenoic acid-derived eicosanoids are less biologically active than arachidonic acid-derived eicosanoids. However, in some case, they have the same potency. One of such example is the inhibition of the Tumor Necrosis Factor-α (TNF-α) production.
Eicosanoids derived from EPA and DHA
EPA and DHA-derived eicosanoids such as resolvins and protectins are some of the eicosanoids that have been shown to possess anti-inflammatory effects. For example, revolvin E1, D1, and protectin D1 have been found to inhibit transendothelial migration of the neutrophils thereby preventing the neutrophilic infiltration at the inflammatory site. In addition to these, revolving D1 has been shown to inhibit interleukin (IL)-1β production while protectin D1 inhibits the production of TNF-α and IL-1β.
Inflammatory gene expression follows NFκB pathway
Nuclear Factor κB (NF κB) is a potential transcription factor that is involved in the upregulation of the inflammatory mediators such as cytokines, adhesion molecules, and COX-2 genes. Signaling cascade begins when the extracellular inflammatory stimuli phosphorylate the inhibitory subunit of the NFκB. Phosphorylated inhibitory subunit of the NFκB dissociates allowing the translocation of its remaining part to the nucleus.
Bacterial endotoxin, lipopolysaccharide (LPS), induces the inflammation by activating NFκB. An in vitro study reveals that omega 3 fatty acids (EPA and DHA) can also inhibit the LPS-induced production of the inflammatory proteins such as COX-2, nitric oxide synthase and some inflammatory mediators such as TNF-α and interleukins in various inflammatory cells. It is found that omega 3 fatty acids decrease the phosphorylation of the inhibitory subunit of the NFκB by activating MAP kinases.