Rheumatology Unit, Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico, 155-00161 Rome, Italy.
Unit of Biology and Genetics of Movement, Department of Movement, Human and Health Sciences, University of Rome "Foro Italico", Piazza Lauro de Bosis, 006-00135 Rome, Italy.
Int J Mol Sci. 2022 Sep 5;23(17):10150. doi: 10.3390/ijms231710150.
The prostacyclin analogue iloprost is used to treat vascular alterations and digital ulcers, the early derangements manifesting in systemic sclerosis (SSc), an autoimmune disease leading to skin and organ fibrosis. Bioindicator(s) of SSc onset and progress are still lacking and the therapeutic approach remains a challenge. The T helper 1 (Th1) chemokine interferon (IFN)γ-induced protein 10 (IP-10/CXCL10) associates with disease progression and worse prognosis. Endothelial cells and fibroblasts, under Th1-dominance, release CXCL10, further enhancing SSc's detrimental status. We analyzed the effect of iloprost on CXCL10 in endothelial cells, dermal fibroblasts, and in the serum of SSc patients. Human endothelial cells and dermal fibroblasts activated with IFNγ/Tumor Necrosis Factor (TNF)α, with/without iloprost, were investigated for CXCL10 secretion/expression and for intracellular signaling cascade underlying chemokine release (Signal Transducer and Activator of Transcription 1, STAT1; Nuclear Factor kappa-light-chain-enhancer of activated B cells, NF-kB; c-Jun NH-terminal kinase, JNK: Phosphatidyl-Inositol 3-kinase (PI3K)/protein kinase B, AKT; Extracellular signal-Regulated Kinase 1/2, ERK1/2). CXCL10 was quantified in sera from 25 patients taking iloprost, satisfying the American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) 2013 classification criteria for SSc, and in sera from 20 SSc sex/age-matched subjects without therapy, previously collected. In human endothelial cells and fibroblasts, iloprost targeted CXCL10, almost preventing IFNγ/TNFα-dependent cascade activation in endothelial cells. In SSc subjects taking iloprost, serum CXCL10 was lower. These in vitro and in vivo data suggest a potential role of iloprost to limit CXCL10 at local vascular/dermal and systemic levels in SSc and warrant further translational research aimed to ameliorate SSc understanding/management.
前列环素类似物伊洛前列素用于治疗血管改变和手指溃疡，这些早期紊乱表现为系统性硬化症（SSc），这是一种导致皮肤和器官纤维化的自身免疫性疾病。SSc 发病和进展的生物标志物仍然缺乏，治疗方法仍然是一个挑战。辅助性 T 细胞 1（Th1）趋化因子干扰素（IFN）γ诱导蛋白 10（IP-10/CXCL10）与疾病进展和预后不良相关。在 Th1 优势下，内皮细胞和成纤维细胞释放 CXCL10，进一步增强了 SSc 的有害状态。我们分析了伊洛前列素对内皮细胞、真皮成纤维细胞和 SSc 患者血清中 CXCL10 的影响。用 IFNγ/肿瘤坏死因子（TNF）α激活的人内皮细胞和真皮成纤维细胞，用/不用伊洛前列素，研究其 CXCL10 分泌/表达以及趋化因子释放的细胞内信号级联（信号转导和转录激活因子 1、STAT1；核因子 kappa-轻链增强子的激活 B 细胞、NF-kB；c-Jun N 端激酶、JNK：磷酸肌醇 3-激酶（PI3K）/蛋白激酶 B、AKT；细胞外信号调节激酶 1/2、ERK1/2）。在 25 名接受伊洛前列素治疗的符合美国风湿病学会（ACR）/欧洲风湿病联盟（EULAR）2013 年 SSc 分类标准的患者血清中以及在 20 名未接受治疗的 SSc 性别/年龄匹配的患者血清中定量了 CXCL10。先前收集的。在人内皮细胞和成纤维细胞中，伊洛前列素靶向 CXCL10，几乎阻止了内皮细胞中 IFNγ/TNFα依赖性级联的激活。在接受伊洛前列素治疗的 SSc 患者中，血清 CXCL10 较低。这些体外和体内数据表明，伊洛前列素可能具有限制 SSc 局部血管/真皮和全身水平 CXCL10 的作用，值得进一步开展旨在改善 SSc 理解/管理的转化研究。
