Takinib Inhibits Inflammation in Human Rheumatoid Arthritis Synovial Fibroblasts by Targeting the Janus Kinase-Signal Transducer and Activator of Transcription 3 (JAK/STAT3) Pathway.
Takinib Inhibits Inflammation in Human Rheumatoid Arthritis Synovial Fibroblasts by Targeting the Janus Kinase-Signal Transducer and Activator of Transcription 3 (JAK/STAT3) Pathway.
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DOI：
10.3390/ijms222212580
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发表时间：
2021-11-22
影响因子：
5.6
通讯作者：
Ahmed S
中科院分区：
文献类型：
--
作者：
Panipinto PM;Singh AK;Shaikh FS;Siegel RJ;Chourasia M;Ahmed S
TGF β激活的激酶1（TAK 1）是类风湿性关节炎（RA）和痛风性关节炎等疾病的炎症发病机制的重要参与者。它在丝裂原活化蛋白激酶（MAPK）和核因子κ B（NF-κB）通路之间占据的中心位置使其成为有吸引力的治疗靶点。随着该领域近年来的发展，已经提出了几种新型抑制剂，其具有共价地（如在5 Z-7-oxozeanol（5 Z7 O）的情况下）或可逆地（NG-25）降低TAK 1功能的特异性活性。然而，takinib发挥其抗炎活性的机制仍不清楚。虽然这种抑制剂显示出巨大的前景，但在解决其临床潜力或其在炎症性疾病中的应用之前，有必要对其抑制剂功能及其潜在的脱靶效应进行彻底分析。蛋白质印迹分析显示，takinib意外增加了IL-1β诱导的TAK 1磷酸化（TAK 1磷酸化是其功能潜力的先决条件和指标），同时证明了体外人类风湿性关节炎滑膜成纤维细胞（RASF）中JAK/STAT通路的抑制作用。在THP-1单核细胞源性巨噬细胞中，takinib再次导致脂多糖诱导的TAK 1磷酸化，而不显著抑制TAK 1下游效应物，即c-Jun N-末端激酶（JNK）、磷酸-c-Jun、NF-κB磷酸-p65或磷酸-I κBα。综上所述，这些发现表明takinib通过靶向多种信号通路（最明显的是人RASF中的JAK/STAT通路）来抑制这些细胞中的炎症。
TGF β-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-κB) 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-1β-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-κB phospho-p65 or phospho-IκBα. 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.
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影响因子：
14.8
作者：
Jones DS;Jenney AP;Swantek JL;Burke JM;Lauffenburger DA;Sorger PK
通讯作者：
Sorger PK
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影响因子：
8.6
作者：
Totzke J;Gurbani D;Raphemot R;Hughes PF;Bodoor K;Carlson DA;Loiselle DR;Bera AK;Eibschutz LS;Perkins MM;Eubanks AL;Campbell PL;Fox DA;Westover KD;Haystead TAJ;Derbyshire ER
通讯作者：
Derbyshire ER
影响因子：
50.3
作者：
Bai, Longchuan;Zhou, Haibin;Wang, Shaomeng
通讯作者：
Wang, Shaomeng
NG25是转化生长因子 - 激活激活激酶1的抑制剂，可改善新生儿低氧缺血性渗透性大鼠的神经元凋亡。
影响因子：
3.4
作者：
Wang H;Chen Z;Li Y;Ji Q
通讯作者：
Ji Q
影响因子：
4.8
作者：
Singh, Anil K.;Fechtner, Sabrina;Ahmed, Salahuddin
通讯作者：
Ahmed, Salahuddin