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

ABSTRACT: Although previous studies have proposed plausible mechanisms of the activation of transforming growth factor-?-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)-?1 has a pivotal role for activating TAK1, and thereby regulate NF-?B-dependent gene expressions in inflammatory signaling mediated by TLR4 and TNF-? stimulation. AMPK-?1 specifically interacts with TAK1 and reciprocally regulates their kinase activities. Upon the stimulation of lipopolysaccharide, AMPK-?1-knockdown (AMPK-?1(KD)) or TAK1-knockdown human monocytic THP-1 cells exhibit a dramatic reduction in the TAK1 or AMPK-?1 kinase activity, respectively, and subsequent suppressions of its downstream signaling cascades, which further leads to inhibitions of NF-?B and thereby productions of proinflammatory cytokines, such as TNF-?, IL-1?, and IL-6. Importantly, the microarray analysis of AMPK-?1(KD) cells revealed a dramatic reduction in the NF-?B-dependent genes induced by TLR4 and TNF-? stimulation, and the observation was in significant correlation with the results of quantitative real-time PCR. Moreover, AMPK-?1(KD) cells are highly sensitive to the TNF-?-induced apoptosis, which is accompanied with dramatic reductions in the NF-?B-dependent and anti-apoptotic genes. As a result, our data demonstrate that AMPK-?1 as an activating kinase of TAK1 has a key role in mediating inflammatory signals triggered by TLR4 and TNF-?.

SUBMITTER: Kim SY 

PROVIDER: S-EPMC3406594 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature