Fli1 deficiency contributes to the suppression of endothelial CXCL5 expression in systemic sclerosis
Fli1 deficiency contributes to the suppression of endothelial CXCL5 expression in systemic sclerosis
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DOI：
10.1007/s00403-013-1431-9
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发表时间：
2014-05-01
影响因子：
3
通讯作者：
Kadono, Takafumi
中科院分区：
文献类型：
--
作者：
Ichimura, Yohei;Asano, Yoshihide;Kadono, Takafumi
CXCL5 是 CXC 趋化因子的成员，具有中性粒细胞趋化因子和促血管生成特性，与类风湿性关节炎和炎症性肠病的病理性血管生成有关。由于异常血管生成也参与系统性硬化症（SSc）的发展过程，因此我们在本文中测量了 63 名 SSc 和 18 名健康受试者的血清 CXCL5 水平，并研究了其临床意义以及解释 SSc 中 CXCL5 表达改变的机制。 SSc 患者的血清 CXCL5 水平显着低于健康受试者。在弥漫性皮肤SSc（dcSSc）中，血清CXCL5水平在早期（<1年）均匀下降，并且在病程<6年的患者中与病程呈正相关。在非早期 dcSSc（1 年千分之一）中，血清 CXCL5 水平降低与手指溃疡的发生有关。一致地，早期 dcSSc 真皮血管中 CXCL5 蛋白的表达水平降低。重要的是，Fli1 与 CXCL5 启动子结合，其基因沉默显着抑制人真皮微血管内皮细胞中 CXCL5 mRNA 的表达。此外，内皮细胞特异性 Fli1 敲除小鼠（一种 SSc 血管病变动物模型）表现出真皮血管中 CXCL5 表达降低。总的来说，这些结果表明 CXCL5 是血管生成相关基因的成员，其表达至少部分由于 SSc 内皮细胞中 Fli1 缺陷而受到抑制。由于 Fli1 缺陷与 SSc 中的异常血管生成密切相关，因此血清 CXCL5 水平可能反向反映 SSc 血管病变的严重程度。
CXCL5 is a member of CXC chemokines with neutrophilic chemoattractant and pro-angiogenic properties, which has been implicated in the pathological angiogenesis of rheumatoid arthritis and inflammatory bowel diseases. Since aberrant angiogenesis is also involved in the developmental process of systemic sclerosis (SSc), we herein measured serum CXCL5 levels in 63 SSc and 18 healthy subjects and investigated their clinical significance and the mechanism explaining altered expression of CXCL5 in SSc. Serum CXCL5 levels were significantly lower in SSc patients than in healthy subjects. In diffuse cutaneous SSc (dcSSc), serum CXCL5 levels were uniformly decreased in early stage (< 1 year) and positively correlated with disease duration in patients with disease duration of < 6 years. In non-early stage dcSSc (a parts per thousand yen1 year), decreased serum CXCL5 levels were linked to the development of digital ulcers. Consistently, the expression levels of CXCL5 proteins were decreased in dermal blood vessels of early stage dcSSc. Importantly, Fli1 bound to the CXCL5 promoter and its gene silencing significantly suppressed the CXCL5 mRNA expression in human dermal microvascular endothelial cells. Furthermore, endothelial cell-specific Fli1 knockout mice, an animal model of SSc vasculopathy, exhibited decreased CXCL5 expression in dermal blood vessels. Collectively, these results indicate that CXCL5 is a member of angiogenesis-related genes, whose expression is suppressed at least partially due to Fli1 deficiency in SSc endothelial cells. Since Fli1 deficiency is deeply related to aberrant angiogenesis in SSc, it is plausible that serum CXCL5 levels inversely reflect the severity of SSc vasculopathy.