Figure 8.

Schematic model showing role of AMPK-α1 as an upstream kinase of TAK1 in TLR4-mediated signaling pathway. Binding of LPS derived from bacterial components to TLR4 initiates intracellular signaling cascades, initially leading to the recruitment of adapter molecules such as MyD88, IRAKs, and Mal proteins. Two critical events for the activation of TAK1 may occur in the middle of signaling cascades. Upon TLR4 stimulation, the activation of AMPK-α1 is simultaneously induced by LKB1 and Ca²⁺-calmodulin-dependent protein kinase, and then activated AMPK-α1 can induce activation of JNK/p38MAPK pathway, thereby inducing activations of AP-1 components such as c-Jun and c-fos. Simultaneously, activated AMPK-α1 specifically interacts with TAK1 through the molecular interaction between N-terminus of TAK1 and autoinhibitory domain of AMPK-α1, and then AMPK-α1 and TAK1 reciprocally induces phosphorylations of TAK1 for the activation. In turn, the activated TAK1 subsequently induces the phosphorylation of IKKβ, leading to IκB degradation and activation of NF-κB. Subsequently, proinflammatory cytokine genes such as TNF-α, IL-1β, and IL-6 are expressed