TAK1 inhibition ameliorates survival from graft-versus-host disease in an allogeneic murine marrow transplantation model

Kobayashi, Ayako; Kobayashi, Shinichi; Miyai, Kosuke; Osawa, Yukiko; Horiuchi, Toshikatsu; Kato, Shingo; Maekawa, Taira; Yamamura, Takeshi; Watanabe, Junichi; Sato, Ken; Tsuda, Hitoshi; Kimura, Fumihiko

doi:10.1007/s12185-017-2345-7

Cited by 3 publications

(8 citation statements)

References 38 publications

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“…Dysregulated innate immune cells are key players in GvHD pathogenesis by activating APCs in the pro-inflammatory milieu ( 16) and inhibition of inflammatory cytokine signaling could ameliorate GvHD severity in mice and humans (15). Aiming to further understand the role and contribution of innate immune cells in GvHD, Kobayashi et al performed gene expression profiling on monocytes from patients who experienced GvHD after allo-HCT (156). The investigators found increased expression of TGFb-activated kinase 1 (TAK1) and downstream signaling molecules, including TNFa, IL-6 and IL-1b, in monocytes from patients with GvHD compared to patients who did not experience GvHD after allo-HCT.…”

Section: Tgfb-activated Kinase 1 (Tak1)mentioning

confidence: 99%

“…extracellular signal-regulated kinase (ERK) and p38 in toll-like receptor (TLR) signaling (16). Based on its role in mediating inflammatory signaling, inhibition of TAK1 was hypothesized being a novel strategy to ameliorate GvHD severity by reducing pro-inflammatory signaling and T-cell alloreactivity (156).…”

Section: Tgfb-activated Kinase 1 (Tak1)mentioning

confidence: 99%

“…Pro-inflammatory cytokine secretion was suppressed in a concentration-dependent manner. Application of OZ in a major mismatch murine aGvHD model prolonged the survival of GvHD mice, reduced GvHD scores and did result in lower serum levels of pro-inflammatory cytokines (156). In a different study, Mathew and Vinnakota et al investigated the role of microglia in central nervous system (CNS) aGvHD and also found TAK1 being an important mediator of aGvHD-induced neurotoxicity (157).…”

Section: Tgfb-activated Kinase 1 (Tak1)mentioning

confidence: 99%

“…Aiming to further understand the role and contribution of innate immune cells in GvHD, Kobayashi et al. performed gene expression profiling on monocytes from patients who experienced GvHD after allo-HCT ( 156 ). The investigators found increased expression of TGFβ-activated kinase 1 (TAK1) and downstream signaling molecules, including TNFα, IL-6 and IL-1β, in monocytes from patients with GvHD compared to patients who did not experience GvHD after allo-HCT.…”

Section: Tgfβ-activated Kinase 1 (Tak1)mentioning

confidence: 99%

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Kinase Inhibition as Treatment for Acute and Chronic Graft-Versus-Host Disease

Braun

Zeiser

2021

Front. Immunol.

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Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a potentially curative therapy for patients suffering from hematological malignancies via the donor immune system driven graft-versus-leukemia effect. However, the therapy is mainly limited by severe acute and chronic graft-versus-host disease (GvHD), both being life-threatening complications after allo-HCT. GvHD develops when donor T cells do not only recognize remaining tumor cells as foreign, but also the recipient’s tissue, leading to a severe inflammatory disease. Typical GvHD target organs include the skin, liver and intestinal tract. Currently all approved strategies for GvHD treatment are immunosuppressive therapies, with the first-line therapy being glucocorticoids. However, therapeutic options for glucocorticoid-refractory patients are still limited. Novel therapeutic approaches, which reduce GvHD severity while preserving GvL activity, are urgently needed. Targeting kinase activity with small molecule inhibitors has shown promising results in preclinical animal models and clinical trials. Well-studied kinase targets in GvHD include Rho-associated coiled-coil-containing kinase 2 (ROCK2), spleen tyrosine kinase (SYK), Bruton’s tyrosine kinase (BTK) and interleukin-2-inducible T-cell kinase (ITK) to control B- and T-cell activation in acute and chronic GvHD. Janus Kinase 1 (JAK1) and 2 (JAK2) are among the most intensively studied kinases in GvHD due to their importance in cytokine production and inflammatory cell activation and migration. Here, we discuss the role of kinase inhibition as novel treatment strategies for acute and chronic GvHD after allo-HCT.

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Section: Tgfb-activated Kinase 1 (Tak1)mentioning

confidence: 99%

Section: Tgfb-activated Kinase 1 (Tak1)mentioning

confidence: 99%

Section: Tgfb-activated Kinase 1 (Tak1)mentioning

confidence: 99%

Section: Tgfβ-activated Kinase 1 (Tak1)mentioning

confidence: 99%

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Kinase Inhibition as Treatment for Acute and Chronic Graft-Versus-Host Disease

Braun

Zeiser

2021

Front. Immunol.

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“…Trim8 directly ubiquitinates transforming growth factor-beta-activated kinase 1, thus promoting its phosphorylation and activation of downstream c-Jun N-terminal kinase/p38 and NF-κB signalling [11]. The MAP3-kinase TGF-beta-activated kinase 1 (TAK1) critically modulates innate and adaptive immune responses and connects cytokine stimulation with activation of inflammatory signalling pathways, including cell survival, apoptosis, autophagy, oxidative processes, cancer and the immune response [27][28][29][30]. TAK1 is a MAP3K protein and is considered a common upstream molecule in the MKK-JNK/p38 and IKK-NF-κB cascade, which induces activation of downstream JNK and NF-κB signalling [31][32][33].…”

Section: The Effect Of Trim8 On Hepatic I/r Is Mediated By Tak1 Activitymentioning

confidence: 99%

Tripartite Motif 8 Deficiency Relieves Hepatic Ischaemia/reperfusion Injury via TAK1-dependent Signalling Pathways

Qiu¹,

Wang²,

Zhou³

et al. 2019

Int. J. Biol. Sci.

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Tripartite motif (Trim) 8 is an E3 ubiquitin ligase, interacting with and ubiquitinating diverse substrates, and is closely involved in innate immunity. However, the function of Trim8 in hepatic ischaemia/reperfusion (I/R) injury remains largely unknown. The aim of this study is to explore the role of Trim8 in hepatic I/R injury. Trim8 gene knockout mice and primary hepatocytes were used to construct hepatic I/R models. The effect of Trim8 on hepatic I/R injury was analysed via pathological and molecular analyses. The results indicated that Trim8 was significantly upregulated in liver of mice subjected to hepatic I/R injury. Trim8 knockout relieved hepatocyte injury triggered by I/R. Silencing of Trim8 expression alleviated hepatic inflammation responses and inhibited apoptosis in vitro and in vivo. Mechanistically, our study suggests that Trim8 deficiency may elicit hepatic protective effects by inhibiting the activation of transforming growth factor β-activated kinase 1 (TAK1)-p38/JNK signalling pathways. TAK1 was required for Trim8 function in hepatic I/R injury as TAK1 activation abolished Trim8 function in vitro. In conclusion, our study demonstrates that Trim8 deficiency plays a protective role in hepatic I/R injury by inhibiting the activation of TAK1-dependent signalling pathways.

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Tbx5 overexpression in embryoid bodies increases TAK1 expression but does not enhance the differentiation of sinoatrial node cardiomyocytes

et al. 2023

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Genetic studies place Tbx5 at the apex of the sinoatrial node (SAN) transcriptional program. To understand its role in SAN differentiation, clonal embryonic stem (ES) cell lines were made that conditionally overexpress Tbx5, Tbx3, Tbx18, Shox2, Islet-1, and MAP3k7/TAK1. Cardiac cells differentiated using embryoid bodies (EBs). EBs overexpressing Tbx5, Islet1, and TAK1 beat faster than cardiac cells differentiated from control ES cell lines suggesting possible roles in SAN differentiation. Tbx5 overexpressing EBs showed increased expression of TAK1, but cardiomyocytes did not differentiate as SAN cells. EBs showed no change in the expression of the SAN transcription factors Shox2 and Islet1 and decreased expression of the SAN channel protein HCN4. EBs constitutively overexpressing TAK1 direct cardiac differentiation to the SAN fate but have reduced phosphorylation of its targets, p38 and Jnk. This opens the possibility that blocking the phosphorylation of TAK1 targets may have the same impact as forced overexpression. To test this, we treated EBs with 5z-7-Oxozeanol (OXO), an inhibitor of TAK1 phosphorylation. Like TAK1 overexpressing cardiac cells, cardiomyocytes differentiated in the presence of OXO beat faster and showed increased expression of SAN genes (Shox2, HCN4, and Islet1). This suggests that activation of the SAN transcriptional network can be accomplished by blocking the phosphorylation of TAK1.

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TAK1 inhibition ameliorates survival from graft-versus-host disease in an allogeneic murine marrow transplantation model

Cited by 3 publications

References 38 publications

Kinase Inhibition as Treatment for Acute and Chronic Graft-Versus-Host Disease

Kinase Inhibition as Treatment for Acute and Chronic Graft-Versus-Host Disease

Tripartite Motif 8 Deficiency Relieves Hepatic Ischaemia/reperfusion Injury via TAK1-dependent Signalling Pathways

Tbx5 overexpression in embryoid bodies increases TAK1 expression but does not enhance the differentiation of sinoatrial node cardiomyocytes

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