TAK1 Negatively Regulates NF-κB and p38 MAP Kinase Activation in Gr-1+CD11b+ Neutrophils

Ajibade, Adebusola Alagbala; Wang, Qinfu; Cui, Jun; Jia, Zhenquan; Xia, Xiaojun; Wang, Mingjun; Tong, Yanzheng; Wei, Hui; Liu, Dou; Su, Bing; Wang, Helen Yicheng; Wang, Rongfu

doi:10.1016/j.immuni.2011.12.010

Cited by 144 publications

(91 citation statements)

References 48 publications

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“…The mutant mice also showed an enlarged spleen (Fig. 1b), as previously reported34. These results suggest that Tak1 is deleted in the mouse line.…”

Section: Resultssupporting

confidence: 89%

Ablation of Tak1 in osteoclast progenitor leads to defects in skeletal growth and bone remodeling in mice

Qian

et al. 2014

Sci Rep

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Tak1 is a MAPKKK that can be activated by growth factors and cytokines such as RANKL and BMPs and its downstream pathways include NF-κB and JNK/p38 MAPKs. Tak1 is essential for mouse embryonic development and plays critical roles in tissue homeostasis. Previous studies have shown that Tak1 is a positive regulator of osteoclast maturation, yet its roles in bone growth and remodeling have not been assessed, as mature osteoclast-specific Tak1 deletion with Cstk-Cre resulted in runtedness and postnatal lethality. Here we generated osteoclast progenitor (monocyte)-specific Tak1 knockout mice and found that these mice show normal body weight, limb size and fertility, and osteopetrosis with severity similar to that of RANK or RANKL deficient mice. Mechanistically, Tak1 deficiency altered the signaling of NF-κB, p38MAPK, and Smad1/5/8 and the expression of PU.1, MITF, c-Fos, and NFATc1, suggesting that Tak1 regulates osteoclast differentiation at multiple stages via multiple signaling pathways. Moreover, the Tak1 mutant mice showed defects in skull, articular cartilage, and mesenchymal stromal cells. Ex vivo Tak1−/− monocytes also showed enhanced ability in promoting osteogenic differentiation of mesenchymal stromal cells. These findings indicate that Tak1 functions in osteoclastogenesis in a cell-autonomous manner and in osteoblastogenesis and chondrogenesis in non-cell-autonomous manners.

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“…The mutant mice also showed an enlarged spleen (Fig. 1b), as previously reported34. These results suggest that Tak1 is deleted in the mouse line.…”

Section: Resultssupporting

confidence: 89%

Ablation of Tak1 in osteoclast progenitor leads to defects in skeletal growth and bone remodeling in mice

Qian

et al. 2014

Sci Rep

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“…However, myeloid specific deletion of Tak1 in Ptpn6 spin mice still induced disease in about 15–20 percent of the mice. We propose the leaky Lyz2 cre induced deletion of Tak1 in myeloid cells and autoimmunity associated with aged Tak1 fl/fl × Lyz2 cre+ mice for the 15–20% disease observed in otherwise protected Ptpn6 spin × Tak1 fl/fl × Lyz2 cre+ mice (Ajibade et al, 2012; Elefteriou and Yang, 2011; Lamothe et al, 2012). …”

Section: Discussionmentioning

confidence: 92%

Tyrosine Kinase SYK Licenses MyD88 Adaptor Protein to Instigate IL-1α-Mediated Inflammatory Disease

et al. 2017

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SUMMARY Mice carrying a hypomorphic point mutation in the Ptpn6 gene (Ptpn6spin mice) develop an inflammatory skin disease that resembles neutrophilic dermatosis in humans. Here, we demonstrated that interleukin (IL)-1α signaling through IL-1R and MyD88 in both stromal and immune cells drive inflammation in Ptpn6spin mice. We further identified SYK as a critical kinase that phosphorylates MyD88, promoted MyD88-dependent signaling and mediates dermatosis in Ptpn6spin mice. Our studies further demonstrated that SHP1 encoded by Ptpn6 binds and suppresses SYK activation to inhibit MyD88 phosphorylation. Downstream of SHP1 and SYK-dependent counterregulation of MyD88 tyrosine phosphorylation, we have demonstrated that the scaffolding function of receptor interacting protein kinase 1 (RIPK1) and tumor growth factor-β activated kinase 1 (TAK1)-mediating signaling were required to spur inflammatory disease. Overall, these studies identify SHP1 and SYK crosstalk as a critical regulator of MyD88 post-translational modifications and IL-1-driven inflammation.

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“…The TAB1 molecule is a key regulator or adaptor protein in TAK1 phosphorylation processes and its down-stream inflammation cascade reaction, especially in NF-κB activation (Ajibade et al, 2012; Kobayashi et al, 2016). Thus, we investigated whether T11 could directly or indirectly block the activation of NF-κB signaling pathway.…”

Section: Resultsmentioning

confidence: 99%

Triptriolide Alleviates Lipopolysaccharide-Induced Liver Injury by Nrf2 and NF-κB Signaling Pathways

et al. 2018

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Nrf2 (Nuclear Factor Erythroid 2 Related Factor 2) transcription factor not only regulates oxidative stress response, but also represses inflammation by regulating cytokines production and cross-talking with NF-κB signaling pathways. Nrf2 plays an essential role in liver injury induced by oxidative stress and inflammation. Triptriolide (T11) is a minor component of Tripterygium wilfordii Hook F. (TwHF), which can be obtained by hydrolysis reaction of triptolide (T9). The major purpose of this study is to clarify the regulating effects of T11 on oxidative stress and inflammation in vivo and in vitro. LPS-stimulated RAW 264.7 cells were used to verify the regulating effects of T11 on oxidative stress (ROS and Nrf2 signaling pathway) and inflammatory cytokines production (TNF-α, IL-6 and IL-1β). The antioxidant responsive element (ARE) luciferase assay was employed to evaluate Nrf2 activation effect of T11 in HEK-293T cells. Lipopolysaccharides (LPS) induced acute liver injury (ALI) in BALB/c mice were used to study the protective effects (ALT, AST, MDA, SOD, histopathology and neutrophils/macrophages filtration) and the underlying protection mechanisms of ALI amelioration (Nrf2 and NF-κB signaling pathway) of T11. Firstly, the results showed that T11 can not only effectively decrease the productions of inflammatory cytokines (TNF-α, IL-6 and IL-1β), ROS and NO in LPS-stimulated RAW 264.7 cells, but also further significantly increase the activity of Nrf2 in HEK-293T cells. Secondly, the results suggested that T11 could dramatically decrease the oxidative stress responses (SOD and MDA) and inflammation (histopathology, neutrophils/macrophages filtration, TNF-α, IL-6 and IL-1β production) in LPS-induced ALI in BALB/c mice. Finally, the results implied that T11 could dramatically increase Nrf2 protein expression and decrease p-TAK1, p-IκBα and NF-κB protein expression both in vivo and in vitro. In conclusion, our findings indicated that T11 could alleviate LPS induced oxidative stress and inflammation by regulating Nrf2 and NF-κB signaling pathways in vitro and in vivo, which offers a novel insights for the application of TwHF in clinical.

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TAK1 Negatively Regulates NF-κB and p38 MAP Kinase Activation in Gr-1+CD11b+ Neutrophils

Cited by 144 publications

References 48 publications

Ablation of Tak1 in osteoclast progenitor leads to defects in skeletal growth and bone remodeling in mice

Ablation of Tak1 in osteoclast progenitor leads to defects in skeletal growth and bone remodeling in mice

Tyrosine Kinase SYK Licenses MyD88 Adaptor Protein to Instigate IL-1α-Mediated Inflammatory Disease

Triptriolide Alleviates Lipopolysaccharide-Induced Liver Injury by Nrf2 and NF-κB Signaling Pathways

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