AMP-activated protein kinase-α1 as an activating kinase of TGF-β-activated kinase 1 has a key role in inflammatory signals

Although previous studies have proposed plausible mechanisms of the activation of transforming growth factor-beta-activated kinase 1 (TAK1) in inflammatory signals, including Toll-like receptors (TLRs), its activating kinase still remains to be unclear. In the present study, we have provided evidences that AMP-activated protein kinase (AMPK)-alpha 1 has a pivotal role for activating TAK1, and thereby regulate NF-kappa B-dependent gene expressions in inflammatory signaling mediated by TLR4 and TNF-alpha stimulation. AMPK-alpha 1 specifically interacts with TAK1 and reciprocally regulates their kinase activities. Upon the stimulation of lipopolysaccharide, AMPK-alpha 1-knockdown (AMPK-alpha 1(KD)) or TAK1-knockdown human monocytic THP-1 cells exhibit a dramatic reduction in the TAK1 or AMPK-alpha 1 kinase activity, respectively, and subsequent suppressions of its downstream signaling cascades, which further leads to inhibitions of NF-kappa B and thereby productions of proinflammatory cytokines, such as TNF-alpha, IL-1 beta, and IL-6. Importantly, the microarray analysis of AMPK-alpha 1(KD) cells revealed a dramatic reduction in the NF-kappa B-dependent genes induced by TLR4 and TNF-alpha stimulation, and the observation was in significant correlation with the results of quantitative real-time PCR. Moreover, AMPK-alpha 1(KD) cells are highly sensitive to the TNF-alpha-induced apoptosis, which is accompanied with dramatic reductions in the NF-kappa B-dependent and anti-apoptotic genes. As a result, our data demonstrate that AMPK-alpha 1 as an activating kinase of TAK1 has a key role in mediating inflammatory signals triggered by TLR4 and TNF-alpha. Cell Death and Disease (2012) 3, e357; doi:10.1038/cddis.2012.95; published online 26 July 2012