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Transforming growth factor ? activated kinase 1: a potential therapeutic target
for rheumatic diseases
#MMPMID27550296
Fechtner S
; Fox DA
; Ahmed S
Rheumatology (Oxford)
2017[Jul]; 56
(7
): 1060-1068
PMID27550296
show ga
Pro-inflammatory cytokines such as IL-1?, IL-6 and TNF-? are central regulators
of autoinflammatory diseases. While targeting these cytokines has proven to be a
successful clinical strategy, the long-term challenges such as drug resistance,
lack of efficacy and poor clinical outcomes in some patients are some of the
limitations faced by these therapies. This has ignited strategies to reduce
inflammation by potentially targeting a variety of molecules, including cell
surface receptors, signalling proteins and/or transcription factors to minimize
cytokine-induced inflammation and tissue injury. In this regard, transforming
growth factor ? activated kinase 1 (TAK1) is activated in the inflammatory signal
transduction pathways in response to IL-1?, TNF-? or toll-like receptor
stimulation. Because of its ideal position upstream of mitogen-activated protein
kinases and the I?B kinase complex in signalling cascades, targeting TAK1 may be
an attractive strategy for treating diseases characterized by chronic
inflammation. Here, we discuss the emerging role of TAK1 in mediating the IL-1?,
TNF-? and toll-like receptor mediated inflammatory responses in diseases such as
RA, OA, gout and SS. We also review evidence suggesting that TAK1 inhibition may
have potential therapeutic value. Finally, we focus on the current status of the
development of TAK1 inhibitors and suggest further opportunities for testing TAK1
inhibitors in rheumatic diseases.
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