JAK1: Number one in the family; number one in inflammation?

肿瘤抑制因子 贾纳斯激酶 Janus激酶1 酪氨酸激酶2 STAT蛋白 JAK-STAT信号通路 医学 癌症研究 车站3 细胞因子 炎症 信号转导 白细胞介素6 细胞生物学 免疫学 受体 酪氨酸激酶 生物 内科学 生长因子 血小板源性生长因子受体
作者
Francesca Romana Spinelli,Robert A. Colbert,Massimo Gadina
出处
期刊:Rheumatology [Oxford University Press]
卷期号:60 (Supplement_2): ii3-ii10 被引量:31
标识
DOI:10.1093/rheumatology/keab024
摘要

Abstract 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.
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