LL Z1640-2

The MAP3 kinase, TAK1, is known to act upstream of IKK and MAPK cascades in several cell types, and is typically activated in response to cytokines (e.g., TNF, IL-1) and TLR ligands. In this article, we report that in human neutrophils, TAK1 can also be activated by different classes of inflammatory stimuli, namely, chemoattractants and growth factors. After stimulation with such agents, TAK1 becomes rapidly and transiently activated. Blocking TAK1 kinase activity with a highly selective inhibitor (5z-7-oxozeaenol) attenuated the inducible phosphorylation of ERK occurring in response to these stimuli but had little or no effect on that of p38 MAPK or PI3K. Inhibition of TAK1 also impaired MEKK3 (but not MEKK1) activation by fMLF. Moreover, both TAK1 and the MEK/ERK module were found to influence inflammatory cytokine expression and release in fMLF- and GM-CSF-activated neutrophils, whereas the PI3K pathway influenced this response independently of TAK1.

Recently, more and more studies support that inflammation is involved in the pathogenesis of epilepsy. Although TGFβ signaling is involved in epileptogenesis, whether TGFβ-associated neuroinflammation is sufficient to regulate epilepsy remains unknown to date. Furthermore, tumor necrosis factor-α receptor-associated factor-6 (TRAF6), transforming growth factor beta-activated kinase 1 (TAK1), which are the key elements of TGFβ-associated inflammation, is still unclear in epilepsy. Therefore, the present study aimed to explore the role of TRAF6 and TAK1 in pilocarpine-induced epileptic rat model. Firstly, the gene levels and protein expression of TRAF6 and TAK1 were detected in different time points after pilocarpine-induced status epilepticus (SE). 5z-7-oxozeaenol treatment (TAK1 antagonist) was then performed; the changes in TRAF6, TAK1, phosphorylated-TAK1 (P-TAK1), interleukin-1β (IL-1β) levels, neuronal survival and apoptosis, and seizure activity were detected.

TGF-β activated kinase 1 (TAK1) has been shown to play a crucial role in cell death, differentiation, and inflammation. Here, we live-imaged robust TAK1 activation in Lewis lung carcinoma 3LL cells implanted into the subcutaneous tissue of syngeneic C57BL/6 mice and treated with polyinosinic polycytidylic acid (PolyI:C). First, we developed and characterized a Förster resonance energy transfer (FRET)-based biosensor for TAK1 activity. The TAK1 biosensor, named Eevee-TAK1, responded to stress-inducing reagents such as anisomycin, tumor necrosis factor-α (TNF-α), and interleukin1-β (IL-1β). The anisomycin-induced increase in FRET was abolished by the TAK1 inhibitor (5z)-7-oxozeaenol. TAK1 activity in 3LL cells was markedly increased by PolyI:C in the presence of macrophages. 3LL cells expressing Eevee-TAK1 were implanted into mice and observed through imaging window by two-photon excitation microscopy. During the growth of tumor, the 3LL cells at the periphery of the tumor exhibited higher TAK1 activity than the 3LL cells locating at the center of the tumor, suggesting that cells at the periphery of the tumor mass were under stronger stress.

Advanced glycation end products (AGEs), inflammatory-activated macrophages are essential in the initiation and progression of diabetic nephropathy (DN). TGF-β-activated kinase 1 (TAK1) plays a vital role in innate immune responses and inflammation. However, little information has been available about the effects of AGEs on the regulation of TAK1 expression and underlying mechanisms in AGEs-stimulated macrophage activation. We hypothesized TAK1 signal pathway in AGEs conditions could be a vital factor contributing to macrophage activation and inflammation. Thus, in the present study, we used bone marrow-derived macrophages (BMMs) to explore the functional role and potential mechanisms of TAK1 pathway under AGEs conditions. Results indicated that TAK1 played important roles in AGEs-induced mitogen-activated protein kinases (MAPKs) and nuclear factor kappa B protein (NF-κB) activation, which regulated the production of monocyte chemo-attractant protein-1 (MCP-1) and tumor necrosis factor-alpha (TNF-α) in AGEs-stimulated macrophages.