Clinical and pathological significance of interleukin 6 overexpression in systemic sclerosis
Clinical and pathological significance of interleukin 6 overexpression in systemic sclerosis
复制标题
DOI：
10.1136/annrheumdis-2011-200955
复制
发表时间：
2012-07-01
影响因子：
27.4
通讯作者：
Ong, Voon H.
中科院分区：
文献类型：
--
作者：
Khan, Korsa;Xu, Shiwen;Ong, Voon H.
目的探讨白细胞介素6 （IL-6）在系统性硬化症（SSc）中表达改变的潜在临床和病理意义。方法测定SSc患者（n = 68）和健康对照组（n = 15）血清IL-6和可溶性IL-6受体水平。探讨SSc患者血清IL-6水平与C反应蛋白、血小板计数及关键临床转归的关系。同时检测皮肤活检组织中IL-6的表达，并用培养的真皮成纤维细胞进行western blot和反转录PCR分析。评估了IL-6反式信号传导对细胞外基质蛋白产生的影响，并使用药物抑制剂检测了下游信号传导途径。结果血清IL-6水平在SSc患者中经常升高，尤其是伴有血小板增多和急性期标志物升高的弥漫性皮肤SSc （dcSSc）患者。在早期dcSSc患者的皮肤成纤维细胞、单核细胞和内皮细胞中观察到明显的表达。体外实验支持IL-6通过JAK2/STAT3和ERK途径传递信号的有效促纤维化作用。与未升高IL-6水平的患者相比，早期高IL-6表达与3年更严重的皮肤受损伤和更差的长期生存有关。结论我们的研究结果证实了IL-6在dcSSc中的过表达，并支持IL-6作为该疾病临床预后的替代标志物的潜力。这些数据也为靶向IL-6反式信号作为SSc潜在抗纤维化治疗的临床研究提供了理论依据。
Objective To determine the potential clinical and pathological significance of altered expression of interleukin 6 (IL-6) in systemic sclerosis (SSc).Methods Serum IL-6 and soluble IL-6 receptor levels were measured in patients with SSc (n = 68) and healthy controls (n = 15). Associations between serum IL-6 level and C reactive protein, platelet count and key clinical outcomes in SSc were explored. Expression of IL-6 in skin biopsies was also examined and western blot and reverse transcription PCR analysis were performed using cultured dermal fibroblasts. The effect of IL-6 trans-signalling on production of extracellular matrix proteins was assessed and downstream signalling pathways were examined using pharmacological inhibitors.Results Serum IL-6 level was frequently elevated in patients with SSc, particularly in those with diffuse cutaneous SSc (dcSSc) with thrombocytosis and elevated acute phase markers. Prominent expression in the skin was observed in dermal fibroblasts, mononuclear cells and endothelial cells in patients with early dcSSc. In vitro experiments supported a potent profibrotic effect of IL-6 trans-signalling via the JAK2/STAT3 and ERK pathways. High IL-6 expression early in dcSSc appears to be associated with more severe skin involvement at 3 years and worse long-term survival than in those without elevated IL-6 levels.Conclusion Our results confirm the overexpression of IL-6 in dcSSc and support the potential of IL-6 as a surrogate marker for clinical outcome in this disease. The data also provide rationale for clinical studies targeting IL-6 trans-signalling as a potential antifibrotic therapy for SSc.