6.1  Inflammatory-resolving effects induced by PUFAs
Nowadays, the mechanisms of action by which n-3 PUFAs regulate the inflammatory processes are widely investigated. The suppression of inflammation by n-3 PUFAs is associated with one of the following mechanisms (1) competitive inhibition of n-6 PUFA pathway; (2) modification of cell membrane composition; (3) affecting the formation of rafts or (4) direct anti-inflammatory effect of their bioactive metabolites (resolvins, protectins, and maresins) (Poudyal et al., 2011).
It has been demonstrated that the dietary supplementation with DHA and EPA from fish increases in a dose-response manner the content of DHA and EPA in the cell inflammation-responsible phospholipids (Calder, 2017); increased content of DHA or EPA in different tissues, such as adipose tissue or heart was also observed in correlation with their intake (Calder, 2015) (Fig. 3 ).
Fig. 3 The effect of omega-3 fatty acids and polyphenols in the regulation of the inflammatory response. Omega-3 fatty acids inhibit the inflammatory response by inhibiting PGE2 which promotes inflammation and NF-κB either directly, via the interaction with the transcriptional factors PPARs, or by inhibiting TLR2/4 which normally activates NF-κB. Moreover, omega-3 fatty acids regulate inflammation by activating MAPK and GPR120 which in turn inhibits inflammation. Polyphenols inhibit the inflammatory response by directly inhibiting NF-κB, or via the PPARs. They also promote fatty acid b-oxidation and inhibit VCAM-1, ICAM-1, MAPK pathway, PGE2 and COX-2 that all promote chronic inflammation (PGE2 –prostaglandin 2; NF-κB – nuclear factor kappa-light-chain-enhancer of activated B cells; PPARs – peroxisome proliferator-activated receptors; TLR2/4– toll-like receptor; MAPK – mitogen-activated protein kinase; GPR120 – G-protein coupled receptor 120; VCAM-1 – vascular cell adhesion molecule 1; ICAM-1 – intracellular cell adhesion molecule 1; COX-2 – cyclooxygenase 2; TNF-α – tumour necrosis factor alpha; MCP-1 – monocyte chemoattractant protein 1; AMPK – AMP kinase).
These n-3 PUFAs frequently substitute n-6 PUFAs like ARA, resulting in decreased availability of ARA for eicosanoid synthesis. EPA also inhibits ARA metabolism as a competitive substrate for COX-2, decreasing prostaglandin E2 (PGE2) production. In rats, dietary supplementation with ALA inhibits PG biosynthesis from ARA, while equivalent quantities of ALA and LA decreased up to 40% n-6 PUFAs incorporation in phospholipids (Calder, 2017). Furthermore, Rees et al. observed that a daily EPA intake of 2.7 g or 4.05 g for 3 months decreases the PGE2 production by lipopolysaccharide-stimulated mononuclear cells, while a lower dose of 1.35 g did not. EPA was integrated in a linear dose-dependent manner into mononuclear cell phospholipids and plasma. This study suggested a daily threshold in the range of 1.35–2.7 g EPA for the anti-inflammatory action (Rees et al., 2006).
Besides decreasing production of PGE2, DHA and EPA are also substrates for the biosynthesis of lipid derivatives, but the EPA-derived mediators as series-3 prostaglandins (PGD3) or series-5 leukotrienes are typically less biologically potent, having a lower ability to interact with relevant eicosanoid receptors (Calder, 2015). For example, EPA-derived leukotriene B5 (LTB5) is almost 100 times less active as a leukocyte chemoattractant than ARA-derived LTB4 (Calder, 2017). However, in some cases, EPA-derived mediators have similar potency with ARA-derived mediators. It appears that EPA-derived PGD3 inhibits the effect of the ARA-derived PGD2, due to a stronger interaction with the DP1 receptor compared to PGD2 (Wada et al., 2007). In other cases, EPA-derived mediators exhibited a similar magnitude of effect (e.g. inhibition of TNF-α production by blood monocytes) (Dooper et al., 2002).