Dipartimento di Scienze Cliniche Internistiche, Anestesiologiche e Cardiovascolari-Reumatologia, Sapienza Università di Roma, Rome, Italy.
Pediatric Translational Research Branch.
Rheumatology (Oxford). 2021 May 5;60(Suppl 2):ii3-ii10. doi: 10.1093/rheumatology/keab024.
Several cytokines involved in inflammatory pathologies signal via the Janus kinase-signal transducer and activator of transcription pathway. Four JAKs are known: JAK1, JAK2, JAK3 and TYK2. The specific activation of JAKs and STATs determines the biological effects of each cytokine. JAK1 is involved in the signalling of 'γc' receptor cytokines (IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21), pro-inflammatory cytokines including IL-6, as well as IFN. The critical position of JAK1 downstream of these cytokines suggests that JAK1-selective inhibitors are comparable to non-selective ones, without the unwanted consequences of JAK2- or JAK3-blockade. JAK inhibition has led to a better understanding of the biology of synovial inflammation and bone homeostasis. Moreover, the efficacy of non-selective JAK inhibitors and novel JAK1-selective drugs in RA supports a role for JAK1 in its pathogenesis. JAK1-selective drugs are also showing promise in axial spondyloarthritis, suggesting that they may target additional regulatory pathways that impact cytokines such as TNF and IL-17A, which do not use JAKs. Additionally, evidence now supports a JAK1 predominance in the signalling of IL-6 and oncostatin M, and indirectly, of TNF in synovial fibroblasts, macrophages and endothelial cells. Notably, bone homeostasis is also dependent on cytokines relying on JAK1 signalling to promote receptor activator of NF-κB ligand expression in osteoblasts and T cells, contributing to osteoclastogenesis. Here, the contribution of JAK1 over other kinases is unclear. While beneficial effects of JAK inhibitors on bone erosion are supported by preclinical and clinical data, effects on new bone formation in axial spondyloarthritis requires additional study.
几种参与炎症病理的细胞因子通过 Janus 激酶-信号转导和转录激活因子途径信号传递。目前已知有 4 种 JAK：JAK1、JAK2、JAK3 和 TYK2。JAK 和 STAT 的特异性激活决定了每种细胞因子的生物学效应。JAK1 参与“γc”受体细胞因子（IL-2、IL-4、IL-7、IL-9、IL-15 和 IL-21）、促炎细胞因子（包括 IL-6）以及 IFN 的信号传递。这些细胞因子下游的 JAK1 关键位置表明，JAK1 选择性抑制剂与非选择性抑制剂相当，而不会产生 JAK2 或 JAK3 阻断的不良后果。JAK 抑制导致对滑膜炎症和骨稳态生物学的更好理解。此外，RA 中非选择性 JAK 抑制剂和新型 JAK1 选择性药物的疗效支持 JAK1 在其发病机制中的作用。JAK1 选择性药物在轴性脊柱关节炎中也显示出前景，表明它们可能针对影响 TNF 和 IL-17A 等细胞因子的其他调节途径，而这些细胞因子不使用 JAK。此外，现在有证据支持 JAK1 在 IL-6 和 Oncostatin M 的信号传递中占主导地位，并且间接地在滑膜成纤维细胞、巨噬细胞和内皮细胞中对 TNF 起作用。值得注意的是，骨稳态也依赖于依赖 JAK1 信号传导来促进破骨细胞和 T 细胞中核因子-κB 配体表达的细胞因子，有助于破骨细胞形成。在这里，JAK1 相对于其他激酶的贡献尚不清楚。虽然 JAK 抑制剂对骨侵蚀的有益影响得到了临床前和临床数据的支持，但在轴性脊柱关节炎中对新骨形成的影响需要进一步研究。
