The Effect of Lithium on Inflammation-Associated Genes in Lipopolysaccharide-Activated Raw 264.7 Macrophages

Figure 12

Demonstration of the putative mechanism of action of lithium in the NF-κB signalling pathway. The LPS free signalling involves the inhibition of the IRAK proteins in the cytoplasm by Tollip protein; this molecule is known to arrest immune cells in quiescent state in the absence of infection or stimulant. Thus, the inhibition of the IRAK proteins leads to the integrity of IκB; then the entire signalling pathway is inhibited. In the LPS treatment, the adapter molecule (Myd88) is recruited to the receptor; this then recruits the IRAK proteins in association with Tollip protein. Therefore, the IRAK protein phosphorylates TRAF protein which recruits the TAB2 and TAK 1 which phosphorylates activated IKK. The IKK then phosphorylates IκB; this molecule is then tagged for degradation by a ubiquitin. This sequence sequesters the NF-κB in the nucleus leading to the expression of inflammatory genes. The combinatory treatment that includes lithium chloride and LPS is thought to disturb the signalling pathway since lithium showed expression of some inhibitory proteins such as p50, IκB-α, NF-κB, and Tollip (shown by arrows). These inhibitory molecules are the control points of the NF-κB signalling pathway. Overexpression of Tollip protein is thought to disturb the pathway by arresting the IRAK protein and then IκB-α removes the NF-κB from its responsive element by its DNA dissociation ability. Moreover, the p50 homodimer competes for the responsive element with the NF-κB p50-p65 heterodimer.