Abstract
Chronic insult and persistent injury can cause liver inflammation, fibrosis, and carcinogenesis; it can also be associated with metabolic disorders. Identification of critical molecules that link the process of inflammation and carcinogenesis will provide prospective therapeutic targets for liver diseases. Rapid advancements in gene engineering technology have allowed the elucidation of the underlying mechanism of transformation, from inflammation and metabolic disorders to carcinogenesis. Transforming growth factor-β-activated kinase 1 (TAK1) is an upstream intracellular protein kinase of nuclear factor kappa-B (NF-κB) and c-Jun N-terminal kinases, which are activated by numerous cytokines, growth factors, and microbial products. In this study, we highlighted the functional roles of TAK1 and its interaction with transforming growth factor-β, WNT, AMP-activated protein kinase, and NF-κB signaling pathways in liver inflammation, steatosis, fibrosis, and carcinogenesis based on previously published articles.
Highlights
Transforming growth factor-β-activated kinase 1 (TAK1) is a member of the mitogen-activated protein (MAP) kinase kinase kinase (MAP3K) (Ajibade et al, 2012; Cohen and Strickson, 2017)
It was found that the level of TGF-β1 in Kupffer cell-depleted TAK1 HEP mice was lower than that in the control TAK1 HEP mice, which suggests that TGF-β1 is mainly produced by Kupffer cells in TAK1 HEP mice. These findings demonstrate that liver injury in TAK1 HEP mice is related to inflammation and TGF-β1 originating from Kupffer cells induces the activation of hepatic stellate cells (HSCs), resulting in liver fibrosis
TAK1 is a pivotal mediator of innate immunity that can be activated by many factors, including pathogen-associated molecular patterns or damage-associated molecular patterns
Summary
Transforming growth factor-β-activated kinase 1 (TAK1) is a member of the mitogen-activated protein (MAP) kinase kinase kinase (MAP3K) (Ajibade et al, 2012; Cohen and Strickson, 2017). The highly homologous CBM complexes can recruit TAK1 and trigger NF-κB and MAPK signaling pathways by ubiquitin ligases, and eventually promote the expression of inflammation-related genes. The stimulation of exogenous and endogenous ligands, such as microbial products, cytokines, growth factors, TNF-α, and TRAIL can activate TAK1 and subsequent cell death and survival signals (Shim et al, 2005; Mihaly et al, 2014; Ogura et al, 2015).
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