Fechtner Sabrina, Fox David A, Ahmed Salahuddin
Department of Pharmaceutical Sciences, Washington State University College of Pharmacy, Spokane, WA.
Department of Internal Medicine, Division of Rheumatology, University of Michigan Medical School, Ann Arbor, MI, USA.
Rheumatology (Oxford). 2017 Jul 1;56(7):1060-1068. doi: 10.1093/rheumatology/kew301.
Pro-inflammatory cytokines such as IL-1β, IL-6 and TNF-α 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 β activated kinase 1 (TAK1) is activated in the inflammatory signal transduction pathways in response to IL-1β, TNF-α or toll-like receptor stimulation. Because of its ideal position upstream of mitogen-activated protein kinases and the IκB 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-1β, TNF-α 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.
白细胞介素-1β、白细胞介素-6和肿瘤坏死因子-α等促炎细胞因子是自身炎症性疾病的核心调节因子。虽然靶向这些细胞因子已被证明是一种成功的临床策略，但耐药性、缺乏疗效以及一些患者临床结果不佳等长期挑战是这些疗法所面临的部分局限性。这激发了通过潜在靶向多种分子（包括细胞表面受体、信号蛋白和/或转录因子）来减轻炎症的策略，以尽量减少细胞因子诱导的炎症和组织损伤。在这方面，转化生长因子β激活激酶1（TAK1）在炎症信号转导通路中响应白细胞介素-1β、肿瘤坏死因子-α或Toll样受体刺激而被激活。由于其在信号级联反应中位于丝裂原活化蛋白激酶和IκB激酶复合物上游的理想位置，靶向TAK1可能是治疗以慢性炎症为特征的疾病的一种有吸引力的策略。在此，我们讨论TAK1在类风湿关节炎、骨关节炎、痛风和干燥综合征等疾病中介导白细胞介素-1β、肿瘤坏死因子-α和Toll样受体介导的炎症反应中的新作用。我们还综述了表明TAK1抑制可能具有潜在治疗价值的证据。最后，我们关注TAK1抑制剂的研发现状，并提出在风湿性疾病中测试TAK1抑制剂的更多机会。
