Molecular Immunology Section, Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Invest Ophthalmol Vis Sci. 2011 Sep 1;52(9):6978-86. doi: 10.1167/iovs.11-7688.
Suppressors of cytokine signaling (SOCS) proteins regulate the intensity and duration of cytokine signals and defective expression of SOCS1 and SOCS3 has been reported in a number of human diseases. The purpose of this study was to investigate the role of SOCS1 in intraocular inflammatory diseases (uveitis) and whether SOCS1 expression is defective in patients with ocular inflammatory diseases.
Blood from patients with scleritis or healthy human volunteers was analyzed for SOCS expression by RNase protection assay and RT-PCR. The authors generated SOCS1 transgenic rats and mice (SOCS1-Tg), induced experimental autoimmune uveoretinitis (EAU) by active immunization with interphotoreceptor retinal binding protein or adoptive transfer of uveitogenic T cells, and investigated effects of SOCS1 overexpression on EAU. SOCS1-mediated protection of retinal cells from apoptosis was assessed by annexin V staining.
Induction of cytokine-induced SH2 protein was comparable between patients and volunteers, whereas 80% of lymphocytes from patients with scleritis failed to induce SOCS1 in response to IL-2. Compared with wild-type littermates, SOCS1-Tg rats/mice developed less severe EAU. Constitutive overexpression of SOCS1 in retina inhibited expression of chemokines (CCL17, CCL20, CXCL9, CXCL10), reduced Th17/Th1 expansion, and inhibited recruitment of inflammatory cells into the retina. The authors also show that SOCS1 protected retinal cells from staurosporine as well as H₂O₂-induced apoptosis.
Defective expression of SOCS1 in patients with scleritis, taken together with SOCS1-mediated protection of neuroretinal cells from apoptosis, suggest that SOCS1 has neuroprotective function in the retina, implying that administration of SOCS1 mimetic peptides may be useful in treating uveitis or scleritis.
细胞因子信号转导抑制因子（SOCS）蛋白调节细胞因子信号的强度和持续时间，已有报道称 SOCS1 和 SOCS3 的表达缺陷存在于多种人类疾病中。本研究旨在探讨 SOCS1 在眼内炎症性疾病（葡萄膜炎）中的作用，以及 SOCS1 表达是否存在缺陷的患者是否存在眼部炎症性疾病。
通过 RNase 保护分析和 RT-PCR 分析来自巩膜炎患者或健康志愿者的血液中 SOCS 的表达。作者生成 SOCS1 转基因大鼠和小鼠（SOCS1-Tg），通过用光感受器间视网膜结合蛋白主动免疫或过继转输致葡萄膜炎 T 细胞诱导实验性自身免疫性葡萄膜炎（EAU），并研究 SOCS1 过表达对 EAU 的影响。通过 Annexin V 染色评估 SOCS1 对视网膜细胞凋亡的保护作用。
诱导细胞因子诱导的 SH2 蛋白在患者和志愿者之间是可比的，而 80%的来自巩膜炎患者的淋巴细胞在 IL-2 刺激下未能诱导 SOCS1。与野生型同窝仔鼠相比，SOCS1-Tg 大鼠/小鼠发生的 EAU 较轻。视网膜中 SOCS1 的组成性过表达抑制趋化因子（CCL17、CCL20、CXCL9、CXCL10）的表达，减少 Th17/Th1 扩增，并抑制炎症细胞向视网膜募集。作者还表明 SOCS1 可保护视网膜细胞免受 staurosporine 和 H₂O₂诱导的凋亡。
巩膜炎患者 SOCS1 的表达缺陷，加上 SOCS1 介导的对神经视网膜细胞凋亡的保护作用，表明 SOCS1 在视网膜中具有神经保护功能，这意味着 SOCS1 模拟肽的给药可能对治疗葡萄膜炎或巩膜炎有用。
