Department of Pharmaceutical Sciences, Washington State University College of Pharmacy and Pharmaceutical Sciences, Spokane, WA 99202, USA.
Center for Computational Biology and Bioinformatics, Amity Institute of Biotechnology, Amity University Uttar Pradesh, Noida 201301, India.
Int J Mol Sci. 2021 Nov 22;22(22):12580. doi: 10.3390/ijms222212580.
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.
转化生长因子 β 激活激酶 1（TAK1）是类风湿关节炎（RA）和痛风性关节炎等疾病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 kappa B（NF-κB）途径之间的中心位置使其成为一个有吸引力的治疗靶点。随着近年来这一领域的发展，已经提出了几种新型抑制剂，它们具有特定的活性，可以通过共价（如 5Z-7-氧杂唑醇（5Z7O））或可逆（NG-25）的方式降低 TAK1 功能。然而，他拉唑尼发挥抗炎活性的机制仍然难以捉摸。虽然这种抑制剂有很大的应用前景，但在评估其临床潜力或在炎症条件下的应用之前，有必要对其抑制剂功能及其潜在的脱靶效应进行全面分析。通过 Western blot 分析表明，他拉唑尼在体外人类风湿关节炎滑膜成纤维细胞（RASFs）中同时抑制 JAK/STAT 通路的情况下，出乎意料地增加了白细胞介素 1β（IL-1β）诱导的 TAK1 磷酸化，这是其功能潜力的先决条件和指标。在 THP-1 单核细胞衍生的巨噬细胞中，他拉唑尼再次导致脂多糖诱导的 TAK1 磷酸化，而对 TAK1 下游效应物，即 c-Jun N-末端激酶（JNK）、磷酸化 c-Jun、NF-κB 磷酸化 p65 或磷酸化 IκBα，没有明显的抑制作用。总之，这些发现表明，他拉唑尼通过靶向多种信号通路，尤其是人 RASFs 中的 JAK/STAT 通路，抑制这些细胞中的炎症。
