Interaction of Dietary Fatty Acids with Tumour Necrosis Factor Family Cytokines during Colon Inflammation and Cancer

Figure 1

Schematic simplified demonstration of the main mechanisms supposed to be involved in fatty acid and TNF family interaction at different levels of colon epithelial cell organisation. Fibre fermentation product butyrate is transported by SMCT into the cells, where it may inhibit histone deacetylation, activate transcription factor PPARγ, inhibit NFκB, and affect ΔΨmt and expression and balance of pro- and antiapoptotic members of Bcl-2 family proteins. Dietary PUFAs of the n-6 (LA, AA-plant oils) and n-3 series and (EPA and DHA, fish and algal oils) transported into the cells by FAT/CD36 are stored in lipid droplets in TAG form or incorporated into plasma and mitochondrial membrane lipids thus modulating composition and structure of lipid rafts and caveolae. PUFAs are released from membrane phospholipids by PLA2 and metabolized by COX and LOX enzymes to various types of products such as LTs and PGs. PUFAs can also modulate ceramide production and their metabolism is source of ROS and RNS and induces lipid peroxidation. Incorporation of PUFAs into mitochondrial cardiolipins influences mitochondrial metabolism and induction of apoptosis. EPA and DHA activate PPARγ and inhibit NFκB, thus suppressing iNOS expression and RNS production. TNF family cytokines TNF-α, TRAIL, and FasL bind to their receptors TNFR1 and 2, DR4 and DR5, or FasR (CD95), respectively. Programmed cell death is regulated by formation of DISC consisting of FADD and procaspase-8, whose activation may be inhibited by cFLIP. Cleavage of Bid protein to tBid mediates connection between extrinsic and intrinsic (mitochondrial) apoptotic pathway. Changes in mitochondria (involving cardiolipin modulation), mitochondrial transition pore opening, decrease of ΔΨmt, and production of ROS influence the activation of pro- and antiapoptotic proteins of the Bcl-2 family and release of proapoptotic proteins (e.g., cytochrome c) into the cytosol. Subsequent activation of caspase-9 and caspase-3, cleavage of PARP, and execution of apoptosis can be inhibited by IAPs. TNF-α activates NFκB via pathway involving TRADD, RIP, TRAF2, and IKK proteins. The interaction between epithelial cells and cells of immune system, which are the source of inflammatory mediators (IFNγ, IL, and PGE2), is also indicated. The dashed arrows-simplified signalling pathways. AA: arachidonic acid; cFLIP: FLICE-like inhibitory protein; COX: cyclooxygenase; ΔΨmt: mitochondrial membrane potential; DHA: docosahexaenoic acid; DISC: death-inducing signaling complex; DR: death receptor; EPA: eicosapentaenoic acid; FADD: Fas-associated DD protein; FasL: Fas ligand; FasR: Fas receptor; FAT/CD36: fatty acid translocase; IAPs: inhibitor of apoptosis proteins; IKK: inhibitor of NFκB kinase; IFNγ: interferonγ; IL: interleukin; iNOS: inducible nitric oxide synthase; LA: linoleic acid; LOX: lipoxygenase; LT: leukotrienes; NF-κB: nuclear factor κB; PARP: poly-ADP ribose polymerase; PG: prostaglandins; PGE2: prostaglandin E2; PLA2: phospholipase A2; PPARγ: peroxisome proliferator-activated receptor γ; PUFA: polyunsaturated fatty acids; RIP: receptor-interacting protein; RNS: reactive nitrogen species; ROS: reactive oxygen species; SMCT: sodium-coupled monocarboxylate transporters; TNF: tumor necrosis factor; TNFR: tumor necrosis factor receptor; TRADD: TNFR1-associated death domain protein; TRAF2: TNF receptor-associated factor 2; TRAIL: tumour necrosis factor-related apoptosis-inducing ligand.