title: AMP-activated protein kinase-α1 as an activating kinase of TGF-β-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-β-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)-α1 has a pivotal role for activating TAK1, and thereby regulate NF-κB-dependent gene expressions in inflammatory signaling mediated by TLR4 and TNF-α stimulation. AMPK-α1 specifically interacts with TAK1 and reciprocally regulates their kinase activities. Upon the stimulation of lipopolysaccharide, AMPK-α1-knockdown (AMPK-α1(KD)) or TAK1-knockdown human monocytic THP-1 cells exhibit a dramatic reduction in the TAK1 or AMPK-α1 kinase activity, respectively, and subsequent suppressions of its downstream signaling cascades, which further leads to inhibitions of NF-κB and thereby productions of proinflammatory cytokines, such as TNF-α, IL-1β, and IL-6. Importantly, the microarray analysis of AMPK-α1(KD) cells revealed a dramatic reduction in the NF-κB-dependent genes induced by TLR4 and TNF-α stimulation, and the observation was in significant correlation with the results of quantitative real-time PCR. Moreover, AMPK-α1(KD) cells are highly sensitive to the TNF-α-induced apoptosis, which is accompanied with dramatic reductions in the NF-κB-dependent and anti-apoptotic genes. As a result, our data demonstrate that AMPK-α1 as an activating kinase of TAK1 has a key role in mediating inflammatory signals triggered by TLR4 and TNF-α.
authors: Department of Molecular Cell Biology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea.
authors: S Y
authors: SY
authors: Kim
authors: S
authors: S
authors: Jeong
authors: E
authors: E
authors: Jung
authors: K-H
authors: KH
authors: Baik
authors: M H
authors: MH
authors: Chang
authors: S A
authors: SA
authors: Kim
authors: J-H
authors: JH
authors: Shim
authors: E
authors: E
authors: Chun
authors: K-Y
authors: KY
authors: Lee
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis; D002460:Cell Line; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D046228:Microarray Analysis; D016328:NF-kappa B / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D055372:AMP-Activated Protein Kinases; D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D034741:RNA, Small Interfering; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D000099151:MAP Kinase Kinase Kinase 7; C526180:PRKAA1 protein, human