Abstract
Aberrant tumour necrosis factor (TNF) signalling is a hallmark of many inflammatory diseases including rheumatoid arthritis (RA), irritable bowel disease and lupus. Maladaptive TNF signalling can lead to hyper active downstream nuclear factor (NF)-κβ signalling in turn amplifying a cell's inflammatory response and exacerbating disease. Within the TNF intracellular inflammatory signalling cascade, transforming growth factor-β-activated kinase 1 (TAK1) has been shown to play a critical role in mediating signal transduction and downstream NF-κβ activation. Owing to its role in TNF inflammatory signalling, TAK1 has become a potential therapeutic target for the treatment of inflammatory diseases such as RA. This review highlights the current development of targeting the TNF-TAK1 signalling axis as a novel therapeutic strategy for the treatment of inflammatory diseases.
Highlights
Tumour necrosis factor (TNF) is a pleotropic proinflammatory cytokine widely regarded as the master regulator of proinflammatory signalling
AntiTNF-based therapies decrease TNF concentration and function, dampening proinflammatory signalling mediated by nuclear factor (NF)-κβ, p38 and c-JUN N-terminal kinase (JNK)
While polyubiquitination of transforming growth factor-β-activated kinase 1 (TAK1) is required for signal transduction in cells, kinase activity can be modelled by TAK1-TAB1 fusion proteins for kinetic and enzymatic studies [11]
Summary
Tumour necrosis factor (TNF) is a pleotropic proinflammatory cytokine widely regarded as the master regulator of proinflammatory signalling. Anti-TNF targeted biologics, such as etanercept and adalimumab, represent a 25 billion dollar industry with the majority of use in the treatment of rheumatoid arthritis (RA) and other auto-immune indications [2] In these diseases, TNF has been shown to play an integral role in the pathogenesis of aberrant maladaptive inflammatory signalling in the absence of physiological needs. In addition to enzymatic studies, in vitro experiments using cytokine stimulations have shown that TAK1 forms a ternary complex with TAB1 and TAB2/3 and undergoes phosphorylation on residues of its activation loop (Thr 178, Thr 184, Thr 187, Ser 192) and K63-linked polyubiquitination at Lys 158 to be fully functional [9,10]. While polyubiquitination of TAK1 is required for signal transduction in cells, kinase activity can be modelled by TAK1-TAB1 fusion proteins for kinetic and enzymatic studies [11]
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