Iwata Shigeru, Yamaoka Kunihiro, Niiro Hiroaki, Nakano Kazuhisa, Wang Sheau-Pey, Saito Kazuyoshi, Akashi Koichi, Tanaka Yoshiya
The First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
Nihon Rinsho Meneki Gakkai Kaishi. 2012;35(1):56-61. doi: 10.2177/jsci.35.56.
Biological products have proven its high efficacy on autoimmune disease such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Meanwhile, small molecular drugs have attracted attention over the years because of its availability of oral administration and cost effectiveness. Spleen tyrosine kinase (Syk) is a 72 kDa protein tyrosine kinase widely expressed on cells that are involved in the immune system and inflammation such as B cells, T cells, macrophages and synovial fibroblast. Syk is involved in intracellular signaling of the multi-chain immune receptors, including B cell receptor (BCR), ζchain of T-cell receptor (TCR), FcR and integrins, which contains the immune-receptor tyrosine-based activation motif (ITAM). Recently, Syk inhibitor fostamatinib has exerted potent therapeutic efficacy against autoimmune and allergic diseases such as rheumatoid arthritis (RA), bronchial asthma and thrombocytopenic purpura (ITP). Moreover, Syk blockade prevented the development of skin and kidney lesions in lupus-prone mice, however the mechanism of action is unclear. We have revealed that Syk-mediated BCR-signaling is prerequisite for optimal induction of toll-like receptor (TLR)-9, thereby allowing efficient propagation of CD40- and TLR9- signaling in human B cells. These results indicate that inhibition of Syk have a potential to regulate B-cell mediated inflammatory diseases such as SLE. We here document the in vitro and in vivo effects of a Syk inhibitor for the treatment of autoimmune diseases, mainly in RA and SLE.
生物制品已在类风湿关节炎（RA）和系统性红斑狼疮（SLE）等自身免疫性疾病中证明了其高效性。与此同时，小分子药物因其可口服给药且具有成本效益，多年来一直备受关注。脾酪氨酸激酶（Syk）是一种72 kDa的蛋白酪氨酸激酶，广泛表达于参与免疫系统和炎症反应的细胞上，如B细胞、T细胞、巨噬细胞和滑膜成纤维细胞。Syk参与多链免疫受体的细胞内信号传导，包括B细胞受体（BCR）、T细胞受体（TCR）的ζ链、FcR和整合素，这些受体含有基于免疫受体酪氨酸的激活基序（ITAM）。最近，Syk抑制剂福他替尼已对类风湿关节炎（RA）、支气管哮喘和血小板减少性紫癜（ITP）等自身免疫性和过敏性疾病发挥了强大的治疗效果。此外，Syk阻断可预防狼疮易感小鼠皮肤和肾脏病变的发展，但其作用机制尚不清楚。我们已经揭示，Syk介导的BCR信号传导是Toll样受体（TLR）-9最佳诱导的先决条件，从而允许CD40和TLR9信号在人B细胞中有效传播。这些结果表明，抑制Syk有可能调节B细胞介导的炎症性疾病，如SLE。我们在此记录了一种Syk抑制剂在治疗自身免疫性疾病（主要是RA和SLE）中的体外和体内作用。
