Inhibition of JAK-STAT Signaling by Baricitinib Reduces Interferon-γ-Induced CXCL10 Production in Human Salivary Gland Ductal Cells
Inhibition of JAK-STAT Signaling by Baricitinib Reduces Interferon-γ-Induced CXCL10 Production in Human Salivary Gland Ductal Cells
复制标题
DOI：
10.1007/s10753-020-01322-w
复制
发表时间：
2020-08-09
期刊：
影响因子：
5.1
通讯作者：
Azuma, Masayuki
中科院分区：
文献类型：
--
作者：
Aota, Keiko;Yamanoi, Tomoko;Azuma, Masayuki
干燥综合征（SS）是一种针对唾液腺和泪腺的慢性自身免疫性疾病。原发性 SS (pSS) 患者的唇唾液腺 (LSG) 中 C-X-C 基序趋化因子配体 10 (CXCL10) 表达上调，CXCL10 通过免疫细胞积累参与 SS 发病机制。此外，干扰素 (IFN)-gamma 通过 Janus 激酶 (JAK)/信号转导器和转录激活剂 (STAT) 途径增强 CXCL10 的产生。我们研究了巴瑞克替尼（一种选择性 JAK1/2 抑制剂）对 IFN-γ 诱导的 CXCL10 产生和免疫细胞趋化性的影响。我们使用免疫组织化学染色来确定 SS 患者 (n = 12) 和健康对照 (n = 3) LSG 中 JAK1 和 JAK2 的表达水平和定位。然后，我们评估了巴瑞克替尼在永生化正常人唾液腺导管（NS-SV-DC）细胞系中的作用。对 pSS 患者 LSG 的免疫组织化学分析显示，导管细胞和腺泡细胞中分别有强 JAK1 和 JAK2 表达。 Baricitinib 以剂量依赖性方式显着抑制 IFN-γ 诱导的 CXCL10 表达以及永生化人唾液腺导管细胞克隆中的蛋白质水平。此外，蛋白质印迹分析表明，巴瑞克替尼可抑制 IFN-γ 诱导的 STAT1 和 STAT3 磷酸化，且对 STAT1 的作用更强。它还抑制 IFN-γ 介导的 Jurkat T 细胞趋化作用。这些结果表明巴瑞克替尼通过抑制 JAK/STAT 信号传导抑制 IFN-γ 诱导的 CXCL10 表达并减弱免疫细胞趋化性，表明其作为 pSS 治疗策略的潜力。
Sjogren's syndrome (SS) is a chronic autoimmune disease targeting salivary and lacrimal glands. C-X-C motif chemokine ligand 10 (CXCL10) expression is upregulated in lip salivary glands (LSGs) of primary SS (pSS) patients, and CXCL10 involved in SS pathogenesis via immune-cell accumulation. Moreover, interferon (IFN)-gamma enhances CXCL10 production via the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. We investigated the effects of baricitinib, a selective JAK1/2 inhibitor, on both IFN-gamma-induced CXCL10 production and immune-cell chemotaxis. We used immunohistochemical staining to determine the expression levels and localization of JAK1 and JAK2 in LSGs of SS patients (n = 12) and healthy controls (n = 3). We then evaluated the effect of baricitinib in an immortalized normal human salivary gland ductal (NS-SV-DC) cell line. Immunohistochemical analysis of LSGs from pSS patients revealed strong JAK1 and JAK2 expression in ductal and acinar cells, respectively. Baricitinib significantly inhibited IFN-gamma-inducedCXCL10expression as well as the protein levels in an immortalized human salivary gland ductal-cell clone in a dose-dependent manner. Additionally, western blot analysis showed that baricitinib suppressed the IFN-gamma-induced phosphorylation of STAT1 and STAT3, with a stronger effect observed in the case of STAT1. It also inhibited IFN-gamma-mediated chemotaxis of Jurkat T cells. These results suggested that baricitinib suppressed IFN-gamma-inducedCXCL10expression and attenuated immune-cell chemotaxis by inhibiting JAK/STAT signaling, suggesting its potential as a therapeutic strategy for pSS.