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-α1KD) 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-α1KD 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-α1KD 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.

Transforming Growth Factor-β–Activated Kinase 1 Regulates Angiogenesis via AMP-Activated Protein Kinase-α1 and Redox Balance in Endothelial Cells

“…5 The situation is, however, currently confused as some reports place the AMPK upstream of TAK1 in inflammatory signaling pathways, indicating a more complicated interaction between the kinases. 6,7 Our investigation indicates that the AMPK is a TAK1 substrate in growth factor-stimulated endothelial cells as TAK1 inhibition prevented VEGF-induced phosphorylation of the AMPK, as well as its downstream target acetyl-CoA carboxylase.…”

“…40 The expression of SOD2 is regulated by a series of transcription factors, including nuclear factor κB and Forkhead box class O transcription factors. 21 The deletion of both TAK1 and AMPKα1 attenuated SOD2 expression in endothelial cells, and both kinases have been reported previously to target nuclear factor κB 6 and Forkhead box class O. 30,41 There are strong links between SOD2 activity and angiogenesis as the mitochondrial generation of H 2 O 2 by SOD2 has been reported previously to promote endothelial cell sprouting.…”

AMP-activated Kinase (AMPK) Promotes Innate Immunity and Antiviral Defense through Modulation of Stimulator of Interferon Genes (STING) Signaling

“…Macrophages lacking the AMPK␣1 subunit have been shown to exhibit an increased response to LPS (65). Yet, human monocytes in which AMPK␣1 was knocked down exhibit decreased cytokine induction of NF-B-dependent genes when treated with LPS (66). Additionally, mice and macrophages that lack one of the activating kinases of AMPK, CaMKK␤, have a diminished response to LPS (67).…”

Adenosine Monophosphate–Activated Kinase and Its Key Role in Catabolism: Structure, Regulation, Biological Activity, and Pharmacological Activation

“…However, TAK1 has also been shown to directly activate AMPK (Scholz et al, 2010). Additionally, a recent study suggests AMPK acts as an activator of TAK1, and that these two proteins reciprocally regulate their activation (Kim et al, 2012b).…”