Inhibition of transforming growth factor beta-activated kinase 1 confers neuroprotection after traumatic brain injury in rats

Zhang, D.; Hu, Yifeng; Sun, Qing; Zhao, Jinbing; Cong, Zixiang; Liu, Hailiang; Zhou, Meifang; Li, K.; Hang, Chun-Hua

doi:10.1016/j.neuroscience.2013.02.022

Cited by 39 publications

(42 citation statements)

References 41 publications

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“…To determine whether TAK1 mediates the inflammatory immune response in vivo in a CPEB-dependent manner, we used (5Z)-7-oxozeaenol, a resocyclin acid lactone that specifically inhibits TAK1 activity in vitro and in vivo (35,36). Figure 5A shows a Kaplan-Meier curve (29) demonstrating that, as depicted earlier, CPEB KO mice succumb more readily than WT mice to LPS administration.…”

Section: Aberrant Nf-b Signaling In Cpeb-deficient Macrophagesmentioning

confidence: 70%

CPEB Regulation of TAK1 Synthesis Mediates Cytokine Production and the Inflammatory Immune Response

Ivshina

Alexandrov

Vertii

et al. 2015

Molecular and Cellular Biology

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The cytoplasmic-element-binding (CPEB) protein is a sequence-specific RNA-binding protein that regulates cytoplasmic polyadenylation-induced translation. In mouse embryo fibroblasts (MEFs) lacking CPEB, many mRNAs encoding proteins involved in inflammation are misregulated. Correlated with this aberrant translation in MEFs, a macrophage cell line depleted of CPEB and treated with lipopolysaccharide (LPS) to stimulate the inflammatory immune response expresses high levels of interleukin-6 (IL-6), which is due to prolonged nuclear retention of NF-B. Two proteins involved in NF-B nuclear localization and IL-6 expression, IB␣ and transforming growth factor beta-activated kinase 1 (TAK1), are present at excessively low and high steadystate levels, respectively, in LPS-treated CPEB-depleted macrophages. However, only TAK1 has an altered synthesis rate that is CPEB dependent and CPEB/TAK1 double depletion alleviates high IL-6 production. Peritoneal macrophages isolated from CPEB knockout (KO) mice treated with LPS in vitro also have prolonged NF-B nuclear retention and produce high IL-6 levels. LPS-injected CPEB KO mice secrete prodigious amounts of IL-6 and other proinflammatory cytokines and exhibit hypersensitivity to endotoxic shock; these effects are mitigated when the animals are also injected with (5Z)-7-oxozeaenol, a potent and specific inhibitor of TAK1. These data show that CPEB control of TAK1 mRNA translation mediates the inflammatory immune response. Inflammation is triggered by bacterial pathogens, as well as lipopolysaccharide (LPS), a bacterial cell wall component that activates the transcription of multiple inflammatory response genes, including those for cytokines and chemokines (1, 2). Despite the importance of these inflammation mediators for host defense against infection, their excessive production can elicit organ failure and septic shock that results in lethality. Therefore, limitation of cytokine production is essential for the termination of inflammation and the prevention of endotoxic tissue damage (2).The production of inflammatory mediators is controlled at multiple levels, including transcription, translation, and protein stability (3). LPS promotes the nuclear import of NF-B (4) by indirectly regulating the activity of the IB kinase (IKK) complex, which phosphorylates IB␣, a factor that normally retains NF-B in the cytoplasm (5-7). Phosphorylated IB␣ is rapidly destroyed, thereby releasing NF-B to translocate to the nucleus and activate the transcription of target genes (8, 9). A proximal upstream LPSactivated factor is the Toll-like receptor, whose signaling pathway includes transforming growth factor beta-activated kinase 1 (TAK1), a mitogen-activated protein (MAP) kinase kinase kinase (10). TAK1 stimulation of p38 MAP kinase leads to IKK activity and NF-B import. LPS stimulation of TAK1 also triggers the stabilization of many mRNAs, which is dependent upon the interplay of several 3= untranslated region (UTR)-binding proteins such as those that associate with the AU-rich element (ARE) ...

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Section: Aberrant Nf-b Signaling In Cpeb-deficient Macrophagesmentioning

confidence: 70%

CPEB Regulation of TAK1 Synthesis Mediates Cytokine Production and the Inflammatory Immune Response

Ivshina

Alexandrov

Vertii

et al. 2015

Molecular and Cellular Biology

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“…The activated TAK1 in turn activates the NF-B and MAPK pathways (13,14). Recent investigations also demonstrate that inhibition of TAK1 provides neuroprotection in ischemia and traumatic brain injury (15)(16)(17). Taking into account this background, the present study aimed to evaluate whether TAK1 is activated after SAH.…”

Section: Subarachnoid Hemorrhage (Sah)mentioning

confidence: 98%

“…This dose was based on our prior published work using OZ in the traumatic brain injury model (15). Coordinates for the injection placement were 1.0 mm posterior to bregma, 1.4 mm lateral to midline, and 4.4 mm below the skull surface, and the injection duration was 10 min.…”

Section: Animals and Subarachnoid Hemorrhage Model-malementioning

confidence: 99%

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TGFβ-activated Kinase 1 (TAK1) Inhibition by 5Z-7-Oxozeaenol Attenuates Early Brain Injury after Experimental Subarachnoid Hemorrhage

Zhang

Huang

et al. 2015

Journal of Biological Chemistry

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Background: Role of TGF␤-activated kinase 1 (TAK1) in the pathogenesis of early brain injury after subarachnoid hemorrhage (SAH) has not been reported. Results: TAK1 inhibition attenuates early brain injury and improves neurological deficits after SAH. Conclusion: TAK1 inhibition exhibits neuro-protective effects possibly through anti-apoptotic function. Significance: These results provide a novel target for SAH treatment.

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“…In the present study, we demonstrate that deletion of Tak1 protects cells from ER stress, both in an in vitro cell culture system and in the CNS. Importantly, Tak1 nKO mice did not show overt histopathological abnormalities, and pharmacological inhibition of TAK1 in the brain is reported not to cause adverse effects but rather to be associated with resistance in the mouse model of cerebral ischemia and experimental traumatic brain injury (Neubert et al, 2011;Zhang et al, 2013). Thus, TAK1 is likely to be a low-risk target for therapeutic approaches in the brain.…”

Section: Tak1 Deficiency Increases Er Volumementioning

confidence: 97%

TAK1 determines susceptibility to endoplasmic reticulum stress and hypothalamic leptin resistance

Sai

Morioka

Takaesu

et al. 2016

Journal of Cell Science

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Sustained endoplasmic reticulum (ER) stress disrupts normal cellular homeostasis and leads to the development of many types of human diseases, including metabolic disorders. TAK1 (also known as MAP3K7) is a member of the mitogen-activated protein kinase kinase kinase (MAP3K) family and is activated by a diverse set of inflammatory stimuli. Here, we demonstrate that TAK1 regulates ER stress and metabolic signaling through modulation of lipid biogenesis. We found that deletion of Tak1 increased ER volume and facilitated ER-stress tolerance in cultured cells, which was mediated by upregulation of sterol-regulatory-element-binding protein (SREBP)-dependent lipogenesis. In the in vivo setting, central nervous system (CNS)-specific Tak1 deletion upregulated SREBP-target lipogenic genes and blocked ER stress in the hypothalamus. Furthermore, CNS-specific Tak1 deletion prevented ER-stress-induced hypothalamic leptin resistance and hyperphagic obesity under a high-fat diet (HFD). Thus, TAK1 is a crucial regulator of ER stress in vivo, which could be a target for alleviation of ER stress and its associated disease conditions.

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Inhibition of transforming growth factor beta-activated kinase 1 confers neuroprotection after traumatic brain injury in rats

Cited by 39 publications

References 41 publications

CPEB Regulation of TAK1 Synthesis Mediates Cytokine Production and the Inflammatory Immune Response

CPEB Regulation of TAK1 Synthesis Mediates Cytokine Production and the Inflammatory Immune Response

TGFβ-activated Kinase 1 (TAK1) Inhibition by 5Z-7-Oxozeaenol Attenuates Early Brain Injury after Experimental Subarachnoid Hemorrhage

TAK1 determines susceptibility to endoplasmic reticulum stress and hypothalamic leptin resistance

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