The IL1-like cytokine IL33 and its receptor ST2 are abnormally expressed in the affected skin and visceral organs of patients with systemic sclerosis
The IL1-like cytokine IL33 and its receptor ST2 are abnormally expressed in the affected skin and visceral organs of patients with systemic sclerosis
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DOI：
10.1136/ard.2009.119321
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发表时间：
2010-03-01
影响因子：
27.4
通讯作者：
Cipriani, Paola
中科院分区：
文献类型：
--
作者：
Manetti, Mirko;Ibba-Manneschi, Lidia;Cipriani, Paola
背景 早期内皮细胞 (EC) 激活/损伤和促纤维化 Th2 相关细胞因子在系统性硬化症 (SSc) 中发挥关键作用。白细胞介素 33 (IL33) 是 IL1 家族的新成员，可通过 ST2 受体促进 Th2 反应和炎症。 IL33也是内皮细胞中染色质相关转录调节因子。目的探讨IL33/ST2轴在SSc中的作用。方法对30例SSc患者(15例早期/15例晚期)和10例健康受试者进行皮肤活检。还分析了 SSc 患者和对照组的肺、肾、心脏、食道、胃、胎盘活检和支气管肺泡灌洗细胞。通过免疫组织学、共聚焦免疫荧光显微镜、蛋白质印迹和RT-PCR研究IL33/ST2的表达。结果在对照受试者的皮肤活检中，在真皮EC和角质形成细胞中发现组成型核IL33蛋白表达，而ST2在EC和成纤维细胞中弱表达。在早期 SSc 患者的皮肤活检中，EC 和表皮中 IL33 蛋白表达下调或缺失，而 IL33 mRNA 正常表达甚至上调。此外，EC、血管周围浸润肥大细胞、CD68阳性巨噬细胞、CD3阳性T细胞、CD20阳性B细胞和活化的成纤维细胞/肌成纤维细胞表现出强烈的ST2表达。在晚期 SSc 患者的皮肤活检中，在大多数 EC 中发现了 IL33，而 ST2 免疫染色较弱。在早期 SSc 中，内皮 IL33 蛋白的缺失和 ST2 的过度表达涉及所有受影响的器官。真皮和肺成纤维细胞在SSc中表达IL33。结论IL33和ST2在SSc中异常表达。在早期 SSc 中，EC 激活/损伤后，IL33 可能从 EC 中动员起来，通过 ST2 在关键的促纤维化参与者（如炎症/免疫细胞和成纤维细胞/肌成纤维细胞）中发出信号。
Background Early endothelial cell (EC) activation/damage and profibrotic Th2-associated cytokines play a pivotal role in systemic sclerosis (SSc). Interleukin 33 (IL33) is a novel member of the IL1 family that promotes Th2 responses and inflammation through the ST2 receptor. IL33 is also a chromatin-associated transcriptional regulator in ECs.Objective To investigate the role of the IL33/ST2 axis in SSc.Methods Skin biopsies were obtained from 30 patients with SSc (15 early/15 late stage) and 10 healthy subjects. Lung, kidney, heart, oesophagus, stomach, placenta biopsies and bronchoalveolar lavage cells from patients with SSc and controls were also analysed. IL33/ST2 expression was investigated by immunohistology, confocal immunofluorescence microscopy, western blotting and RT-PCR.Results In skin biopsies from control subjects, constitutive nuclear IL33 protein expression was found in dermal ECs and keratinocytes, while ST2 was weakly expressed in ECs and fibroblasts. In skin biopsies from patients with early SSc, IL33 protein was downregulated or absent in ECs and epidermis while IL33 mRNA was normally expressed or even upregulated. Moreover, ECs, perivascular infiltrating mast cells, CD68-positive macrophages, CD3-positive T cells, CD20-positive B cells and activated fibroblasts/myofibroblasts exhibited strong ST2 expression. In skin biopsies from patients with late SSc, IL33 was constitutively found in most ECs while ST2 immunostaining was weaker. In early SSc, the loss of endothelial IL33 protein and the overexpression of ST2 involved all affected organs. Dermal and pulmonary fibroblasts showed IL33 expression in SSc.Conclusion IL33 and ST2 are abnormally expressed in SSc. In early SSc, upon EC activation/damage IL33 may be mobilised from ECs to signal through ST2 in key profibrotic players such as inflammatory/immune cells and fibroblasts/myofibroblasts.