Yu Cheng-Rong, Hayashi Kozaburo, Lee Yun Sang, Mahdi Rashid M, Shen De Fen, Chan Chi-Chao, Egwuagu Charles E
Molecular Immunology Section, Laboratory of Immunology, National Eye Institute, National Institutes of Health, Building 10, Room 10N109A, 10 Center Drive, Bethesda, MD, 20892-1857, USA.
Inflammation. 2015 Apr;38(2):555-65. doi: 10.1007/s10753-014-9962-6.
Immunological responses to pathogens are stringently regulated in the eye to prevent excessive inflammation that damage ocular tissues and compromise vision. Suppressors of cytokine signaling (SOCS) regulate intensity/duration of inflammatory responses. We have used SOCS1-deficient mice and retina-specific SOCS1 transgenic rats to investigate roles of SOCS1 in ocular herpes simplex virus (HSV-1) infection and non-infectious uveitis. We also genetically engineered cell-penetrating SOCS proteins (membrane-translocating sequence (MTS)-SOCS1, MTS-SOCS3) and examined whether they can be used to inhibit inflammatory cytokines. Overexpression of SOCS1 in transgenic rat eyes attenuated ocular HSV-1 infection while SOCS1-deficient mice developed severe non-infectious anterior uveitis, suggesting that SOCS1 may contribute to mechanism of ocular immune privilege by regulating trafficking of inflammatory cells into ocular tissues. Furthermore, MTS-SOCS1 inhibited IFN-γ-induced signal transducers and activators of transcription 1 (STAT1) activation by macrophages while MTS-SOCS3 suppressed expansion of pathogenic Th17 cells that mediate uveitis, indicating that MTS-SOCS proteins maybe used to treat ocular inflammatory diseases of infectious or autoimmune etiology.
眼部对病原体的免疫反应受到严格调控，以防止过度炎症对眼组织造成损伤并损害视力。细胞因子信号抑制因子（SOCS）调节炎症反应的强度/持续时间。我们利用SOCS1基因缺陷小鼠和视网膜特异性SOCS1转基因大鼠，研究SOCS1在眼部单纯疱疹病毒（HSV-1）感染和非感染性葡萄膜炎中的作用。我们还通过基因工程构建了细胞穿透性SOCS蛋白（膜转位序列（MTS）-SOCS1、MTS-SOCS3），并研究它们是否可用于抑制炎性细胞因子。SOCS1在转基因大鼠眼中的过表达减轻了眼部HSV-1感染，而SOCS1基因缺陷小鼠则发生了严重的非感染性前葡萄膜炎，这表明SOCS1可能通过调节炎性细胞向眼组织的迁移，参与眼部免疫赦免机制。此外，MTS-SOCS1抑制巨噬细胞中IFN-γ诱导的信号转导和转录激活因子1（STAT1）激活，而MTS-SOCS3抑制介导葡萄膜炎的致病性Th17细胞的扩增，这表明MTS-SOCS蛋白可能用于治疗感染性或自身免疫性病因的眼部炎性疾病。
