Enterocyte-Derived TAK1 Signaling Prevents Epithelium Apoptosis and the Development of Ileitis and Colitis

Kajino‐Sakamoto, Rie; Inagaki, Manabu; Lippert, Elisabeth; Akira, Shizuo; Robine, Sylvie; Matsumoto, Kunihiro; Jobin, Christian; Ninomiya‐Tsuji, Jun

doi:10.4049/jimmunol.181.2.1143

Cited by 139 publications

(166 citation statements)

References 37 publications

(49 reference statements)

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“…Nonetheless, these tissue injuries are associated with caspase activation and are not rescued by Ripk3 deletion, indicating that they are primarily apoptosis. 37,49,55,57,[82][83][84][85]88 We note here that the role of TAK1 in vivo may not be limited to prevention of cell death. For example, Tak1-deficient neutrophils hyperproliferate rather than dying spontaneously, leading to splenomegaly and myelomonocytic leukemia.…”

Section: Pathology Of Tak1 Deficiency In a Variety Of Tissue In Mousementioning

confidence: 80%

“…55,56 Hepatocyte-specific deletion of TAK1 triggers TNFa-dependent liver injury and hepatocellular carcinoma within 6 weeks of age, whereas loss of NF-kB activation by NEMO deletion causes much milder liver injury around 20 weeks of age. 57 Furthermore, it appears that NF-kB activity is not always regulated by TAK1 in some tissues in vivo.…”

Section: Tak1 Control Of Cell Death Sr Mihaly Et Almentioning

confidence: 99%

“…Epithelial cellspecific deletion of Tak1 in the epidermis or intestinal epithelium causes caspase activation and cell death leading to severe inflammation, which resembles psoriasis in the case of epidermal Tak1 deletion, and inflammatory bowel disease (IBD) in intestinal epithelium Tak1 deletion. 55,65,66,82 Endothelium-specific deletion of Tak1 causes endothelial cell death and blood vessel regression around E10-11, which results in embryonic lethality. 37 Hepatocyte-specific deletion of Tak1 also causes cell death and liver injury.…”

Section: Pathology Of Tak1 Deficiency In a Variety Of Tissue In Mousementioning

confidence: 99%

“…57,83 Hematopoietic-specific Tak1 deletion depletes hematopoietic progenitor cells, T cells and macrophages. [10][11][12]58,[84][85][86][87] Deletion of TNF receptor 1 (Tnfr1) largely rescues these injuries and animal mortalities, 37,55,57,[82][83][84][85] demonstrating that TNFa is the major killer of Tak1-deficient cells in these tissues. However, some Tak1-deficient tissue injuries are still observed in Tnfr1-null background.…”

Section: Pathology Of Tak1 Deficiency In a Variety Of Tissue In Mousementioning

confidence: 99%

“…82,92 Inducible deletion of Tak1 or caspase-8 in the intestinal epithelium causes IBD-like intestinal inflammation, which is associated with loss of a specific cell type known as paneth cells. 55,93 Similarly, epidermal-and intestinal epithelium-specific deletion of Fadd, which abrogates caspase-8 activation, causes inflammatory skin disease and IBD-like ileitis. 94,95 Although either Tak1 or Fadd/caspase-8 deletion causes cell death, the types of cell death are different.…”

Section: Pathology Of Tak1 Deficiency In a Variety Of Tissue In Mousementioning

confidence: 99%

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TAK1 control of cell death

2014

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Programmed cell death, a physiologic process for removing cells, is critically important in normal development and for elimination of damaged cells. Conversely, unattended cell death contributes to a variety of human disease pathogenesis. Thus, precise understanding of molecular mechanisms underlying control of cell death is important and relevant to public health. Recent studies emphasize that transforming growth factor-b-activated kinase 1 (TAK1) is a central regulator of cell death and is activated through a diverse set of intra-and extracellular stimuli. The physiologic importance of TAK1 and TAK1-binding proteins in cell survival and death has been demonstrated using a number of genetically engineered mice. These studies uncover an indispensable role of TAK1 and its binding proteins for maintenance of cell viability and tissue homeostasis in a variety of organs. TAK1 is known to control cell viability and inflammation through activating downstream effectors such as NF-jB and mitogen-activated protein kinases (MAPKs). It is also emerging that TAK1 regulates cell survival not solely through NF-jB but also through NF-jB-independent pathways such as oxidative stress and receptor-interacting protein kinase 1 (RIPK1) kinase activity-dependent pathway. Moreover, recent studies have identified TAK1's seemingly paradoxical role to induce programmed necrosis, also referred to as necroptosis. This review summarizes the consequences of TAK1 deficiency in different cell and tissue types from the perspective of cell death and also focuses on the mechanism by which TAK1 complex inhibits or promotes programmed cell death. This review serves to synthesize our current understanding of TAK1 in cell survival and death to identify promising directions for future research and TAK1's potential relevance to human disease pathogenesis.

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Section: Pathology Of Tak1 Deficiency In a Variety Of Tissue In Mousementioning

confidence: 80%

Section: Tak1 Control Of Cell Death Sr Mihaly Et Almentioning

confidence: 99%

Section: Pathology Of Tak1 Deficiency In a Variety Of Tissue In Mousementioning

confidence: 99%

Section: Pathology Of Tak1 Deficiency In a Variety Of Tissue In Mousementioning

confidence: 99%

Section: Pathology Of Tak1 Deficiency In a Variety Of Tissue In Mousementioning

confidence: 99%

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TAK1 control of cell death

2014

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Compound mutations in Bmpr1a and Tak1 synergize facial deformities via increased cell death

Liu

Hayano

Pan

et al. 2018

Genesis

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BMP signaling plays a critical role in craniofacial development. Augmentation of BMPR1A signaling through neural crest-specific expression of constitutively active Bmpr1a (caBmpr1a) results in craniofacial deformities in mice. To investigate whether deletion of Tak1 may rescue the craniofacial deformities caused by enhanced Smad-dependent signaling through caBMPR1A, we generated embryos to activate transcription of caBmpr1a transgene and ablate Tak1 in neural crest derivatives at the same time. We found that deformities of the double mutant mice showed more severe than those with each single mutation, including median facial cleft and cleft palate. We found higher levels of cell death in the medial nasal and the lateral nasal processes at E10.5 in association with higher levels of p53 in the double mutant embryos. We also found higher levels of pSmad1/5/9 in the lateral nasal processes at E10.5 in the double mutant embryos. Western analyses revealed that double mutant embryos showed similar degrees of upregulation of pSmad1/5/9 with caBmpr1a or Tak1-cKO embryos while the double mutant embryos showed higher levels of phospho-p38 than caBmpr1a or Tak1-cKO embryos at E17.5, but not at E10.5. It suggested that deletion of Tak1 aggravates the craniofacial deformities of the caBmpr1a mutants by increasing p53 and phospho-p38 at different stage of embryogenesis.

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The contribution of toll‐like receptor signaling to the development of liver fibrosis and cancer in hepatocyte‐specific TAK1‐deleted mice

Song

Yang

Inokuchi-Shimizu

et al. 2017

Intl Journal of Cancer

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Hepatocyte death is associated with liver inflammation, fibrosis and hepatocellular carcinoma (HCC). Damaged cells trigger inflammation through activation of Toll-like receptors (TLRs). Although the role of TLR4 in HCC development has been reported, the role of TLR9 in the development of HCC remains elusive. To investigate the role of TLR4 and TLR9 signaling in liver inflammation-fibrosis-cancer axis, we took advantage of mice with hepatic deletion of transforming growth factor-β- activated kinase 1 (Tak1ΔHep) that develop spontaneous liver injury, inflammation, fibrosis, and HCC, recapitulating the pathology of human HCC. We generated double knockout mice lacking genes of our interest with hepatic Tak1. Tak1ΔHep mice and Tlr4-deficient Tak1ΔHep mice had similar serum ALT levels, but Tlr4-deficient Tak1ΔHep mice exhibited significantly reduced macrophage infiltration, myofibroblast activation and tumor formation. Ablation of TLR9 reduced spontaneous liver injury, inflammation, fibrosis, and cancer development in Tak1ΔHep mice. In addition, the common adaptor, myeloid differentiation factor 88 (MyD88)-deficient Tak1ΔHep mice also attenuated liver injury, macrophage recruitment, collagen deposition, and tumor growth compared with control Tak1ΔHep mice. Genetic ablation of TNF receptor type I (TNFR) in Tak1ΔHep mice remarkably reduced liver inflammation-fibrosis-cancer axis. Surprisingly, disruption of interleukin-1 receptor (IL-1R) had no effect on liver injury and tumor formation, although Il1r-deficient Tak1ΔHep showed attenuated macrophage infiltration and collagen deposition. In conclusion, TLR4- and TLR9-MyD88 are driving forces of progression to HCC accompanied by liver inflammation and fibrosis in Tak1ΔHep mice. Importantly, TLR4 and TLR9 downstream TNFR, but not IL-1R signaling is crucial for the development of HCC in Tak1ΔHep mice.

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Enterocyte-Derived TAK1 Signaling Prevents Epithelium Apoptosis and the Development of Ileitis and Colitis

Cited by 139 publications

References 37 publications

TAK1 control of cell death

TAK1 control of cell death

Compound mutations in Bmpr1a and Tak1 synergize facial deformities via increased cell death

The contribution of toll‐like receptor signaling to the development of liver fibrosis and cancer in hepatocyte‐specific TAK1‐deleted mice

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