NFkB pathway

The third signalling pathway of TRIF utilises its C-terminus. This region contains a RJQP homology interaction motif (RHIM) that binds RJQP-1 and REP-3. RIP-1 phosphorylates IKK-(3 and the NFkB pathway can be activated. REP-3 is a negative regulator of TREF competing for REP-1 [2]. 

When TRAF2 and RlPl bind to the complex, two sequential pathways are activated the NFkB pathway and the activated caspase-8 pathway. In the first step of the NFkB pathway, TNF activates the IxBa pathway in a process that depends on the degradation of the inhibitor IkB by the proteasome. The Ikk complex (IkB kinase) mediates the phosphorylation of the inhibitor IkB. The Ikk complex is formed by two related IkB kinases, iKBa and kBfl, and NFkB essential modulator (NEMO), a regulatory protein also known as kBy. The roles of TRAF2 and RIP in the Ikk complex are recmitment and stabilization, respeetively (Devin et al., 2003). 

It is too early to definitively identify the molecular mechanism(s) by which CLA, or specific isomers thereof, modulate immune reactivity and reduce disease. Peroxisomal proliferator-activated receptor-y (PPAR-y) activation has been proposed as a mechanism by which CLA exerts some of its biological effects (23). Although PPAR-y may play a role in some of the effects caused by dietary CLA, and these effects could be mediated via the downregulation of the NFkB pathway (24), there are some inconsistencies in the isomer-specific effects on the regulation of COX-2 and some of the products of the NFkB pathway. For example, Yu et al. (23) demonstrated that both the t9,cll and the tl0,cl2 isomers of CLA increase PPAR-y, and decrease TNFa however, only the c9,tll isomer decreased endotoxin-induced TNFa (12). If CLA-fed animals are more resistant to endotoxin (above) and if endotoxin downregulates PPAR-y (24), could PPAR-y regulation explain the wide array of effects attributed to dietary CLA ... 

The role of NFkB has been reviewed in ref. 205. NFkB is a key regulator of inflammation, immune responses, cell survival, and cell proliferation inhibition of the NFkB pathway in macrophages leads to more severe atherosclerosis in low density lipoprotein receptor (LDLR) deficient mice, possibly by affecting the pro- and anti-inflammatory balance that controls the development of atherosclerosis (reduced production of LPS-stimulated TNF, and reduction in IL-10) (206). 

Curcumin inhibits the production of many cytokines that are under the control of the NFkB pathway as shown in various cell types. Besides EL-Ip andTNF-a, it inhibits the production of IL-2, IL-4, IL-5 and IL-8 by human monocytes and macrophages (19, 20). Curcumin also inhibits IL-12 production, though not IL-10, in murine macrophages. It may bias the T-helper 1/T helper 2 balance by decreasing the production of IFNy and increasing the production of IL-4 (21, 22). For chemotaxis, in rat and human intestinal epithelial cells, IL-ip-mediated expression of IL-8 is suppressed by curcumin (23). in human osteoblasts, epinephrine-induced expression of IL-6 and IL-12 is also inhibited by curcumin though it is via the AP-1 pathway, rather than the NF-kB pathway (24). 

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