期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 22, 期 22, 页码 -出版社
MDPI
DOI: 10.3390/ijms222212580
关键词
takinib; TAK1; rheumatoid arthritis; RASFs; THP-1; MAPK; NF-kB; JAK/STAT
资金
- NIH R01 [AR072615]
TGF beta-activated kinase 1 (TAK1) is a key player in inflammatory diseases such as rheumatoid arthritis (RA) and gouty arthritis. The role of takinib in inhibiting inflammation involves targeting multiple signaling pathways, particularly the JAK/STAT pathway in human RASFs.
TGF beta-activated kinase 1 (TAK1) is an important participant in inflammatory pathogenesis for diseases such as rheumatoid arthritis (RA) and gouty arthritis. The central position it occupies between the mitogen activated protein kinase (MAPK) and nuclear factor kappa B (NF-kappa B) pathways makes it an attractive therapeutic target. As this field has developed in recent years, several novel inhibitors have been presented as having specific activity that reduces the TAK1 function either covalently as in the case of 5Z-7-oxozeanol (5Z7O) or reversibly (NG-25). However, the mechanism through which takinib elicits its anti-inflammatory activity remains elusive. While this inhibitor shows great promise, a thorough analysis of its inhibitor function and its potential off-target effects is necessary before addressing its clinical potential or its use in inflammatory conditions. An analysis through Western blot showed an unexpected increase in IL-1 beta-induced TAK1 phosphorylation-a prerequisite for and indicator of its functional potential-by takinib while simultaneously demonstrating the inhibition of the JAK/STAT pathway in human rheumatoid arthritis synovial fibroblasts (RASFs) in vitro. In THP-1 monocyte-derived macrophages, takinib again led to the lipopolysaccharide-induced phosphorylation of TAK1 without a marked inhibition of the TAK1 downstream effectors, namely, of c-Jun N-terminal kinase (JNK), phospho-c-Jun, NF-kappa B phospho-p65 or phospho-I kappa B alpha. Taken together, these findings indicate that takinib inhibits inflammation in these cells by targeting multiple signaling pathways, most notably the JAK/STAT pathway in human RASFs.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据