Suppressors of Cytokine Signalling (SOCS) have Neuroprotective Roles in Retina

细胞因子信号传导抑制剂 (SOCS) 对视网膜具有神经保护作用

• 批准号: 7594053
• 负责人: Charles E Egwuagu
• 金额: $ 54.09万
• 依托单位: NATIONAL EYE INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7594053
• 关键词: AKT inhibition; Allergic; Amino Acids; Area; Autoimmune Diseases; Belief; Blood; Boxing; C-terminal; CISH gene; Cells; Communication; Condition; Cytokine Inducible SH2-Containing Protein; Cytokine Receptors; Diabetes Mellitus; Diabetic Retinopathy; Disease; EGF gene; Erythropoietin; Family; Feedback; Gene Expression; Goals; Growth Factor; Human; Inflammation; Inflammatory; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Janus kinase; Length; Liver; Lymphoid; Malignant Neoplasms; Mediating; Metabolic syndrome; Modeling; Mus; N-terminal; Obesity; Pathologic; Pattern; Platelet-Derived Growth Factor; Play; Polycystic Kidney Diseases; Protein Tyrosine Kinase; Proteins; Proto-Oncogene Proteins c-akt; Regulation; Retina; Retinal; Role; Severities; Signal Transduction; Signaling Protein; Suppressor of Cytokine Signaling Family Protein; T-Lymphocyte; Uveitis; autoimmune uveitis; cytokine; enhancing factor; injured; insulin signaling; interest; lymph nodes; member; protein function; receptor; stem

Suppressor of cytokine signaling (SOCS) family of proteins contain eight members (SOCS1 through SOCS7; and cytokine-induced SH2-containing protein or CIS), each of which contains a conserved central Src homology 2 (SH2) domain flanked by a variable length N-terminal domain and a 40-amino acid C-terminal domain called the SOCS box. SOCS proteins regulate signals transmitted by hemopoietin cytokine receptors with associated JAK kinases. Signals induced by insulin and growth factors whose receptors possess intrinsic tyrosine kinase activity (IGF-1, FGFs, PDGF, EGF and erythropoietin) are also under feedback regulation by SOCS proteins. Significant interest in SOCS family stems from the belief that SOCS proteins function to integrate multiple cytokine/growth factor signals and mediate cross-communication between antagonistic factors. Importance of SOCS proteins is underscored by the wide array of pathologic conditions that result from deletion of SOCS genes or dysregulation of SOCS genes expression. These include allergic and autoimmune diseases, insulin resistance, diabetes, liver degeneration, lymphoid deficiencies, polycystic kidney disease and cancer. In this study, our focus has been in two areas: (i) Potential neuroprotective roles of SOCS proteins. We examined the temporal expression of inflammatory cytokines and SOCS genes in the retina, blood and lymph nodes from mice with experimental autoimmune uveitis (EAU), a T cell-mediated disease that serves as model of human uveitis to determine whether the pattern of SOCS expression correlates with severity of EAU or host protective mechanisms. We found that SOCS1 and SOCS3 proteins that are induced by inflammatory cytokines play important roles in mitigating uveitis by negative regulation of IFNg activity during EAU while SOCS5 that is constitutively expressed in the retina exerts a protective function. These results suggest that SOCS proteins may function to curtail the duration of deleterious activities of pro-inflammatory cytokines in the retina and augment levels of trophic factors that enhance survival of injured retinal cells. (ii) Potential role of SOCS proteins in insulin-resistance and diabetic retinopathy. Our studies reveal that although SOCS1, SOCS3 or CIS mRNAs or proteins are barely detectable in the retina, their expression is markedly induced during inflammation. In addition, IFNg produced by inflammatory cells synergizes with insulin to further enhance SOCS1 and SOCS3 expression in retina and induces the inhibition of AKT (PKB) activation by insulin in the retina. In contrast to the cytokine-inducible SOCS (SOCS1, SOCS3, CIS), we found that SOCS5, SOCS6 and SOCS7 proteins are constitutively expressed in the retina and the depletion of endogenous SOCS6 levels in retinal cells induces inhibition of insulin-induced AKT activation. These results suggest that inflammatory molecules such as IFNg may promote insulin resistance in the retina by inducing expression of CIS, SOCS1 or SOCS3 while constitutive SOCS proteins such as SOCS6 may promote insulin signaling in retina and may have neuroprotective functions.

细胞因子信号传导抑制蛋白（SOCS）家族包含8个成员（SOCS 1至SOCS 7;以及含丝氨酸诱导的SH 2蛋白或CIS），每个成员包含保守的中心Src同源2（SH 2）结构域，两侧是可变长度的N-末端结构域和40个氨基酸的C-末端结构域，称为SOCS盒。SOCS蛋白调节促红细胞生成素细胞因子受体与相关JAK激酶传递的信号。胰岛素和生长因子（其受体具有内在酪氨酸激酶活性）（IGF-1，FGF，PDGF，EGF和促红细胞生成素）诱导的信号也受到SOCS蛋白的反馈调节。对SOCS家族的重大兴趣源于人们认为SOCS蛋白具有整合多种细胞因子/生长因子信号并介导拮抗因子之间的交叉通讯的功能。SOCS蛋白的重要性通过由SOCS基因的缺失或SOCS基因表达的失调引起的广泛的病理状况来强调。这些疾病包括过敏性和自身免疫性疾病、胰岛素抵抗、糖尿病、肝变性、淋巴缺陷、多囊肾病和癌症。在这项研究中，我们的重点是两个领域：（i）SOCS蛋白的潜在神经保护作用。我们研究了实验性自身免疫性葡萄膜炎（EAU）小鼠视网膜、血液和淋巴结中炎性细胞因子和SOCS基因的时间表达，该疾病是一种T细胞介导的疾病，可作为人类葡萄膜炎的模型，以确定SOCS表达模式是否与EAU的严重程度或宿主保护机制相关。我们发现，由炎性细胞因子诱导的SOCS 1和SOCS 3蛋白通过在EAU期间负调节IFNg活性在减轻葡萄膜炎中起重要作用，而在视网膜中组成性表达的SOCS 5发挥保护功能。这些结果表明，SOCS蛋白可能起到缩短视网膜中促炎细胞因子的有害活性的持续时间和增加营养因子的水平的作用，所述营养因子增强受损视网膜细胞的存活。(ii)SOCS蛋白在胰岛素抵抗和糖尿病视网膜病变中的潜在作用我们的研究表明，尽管SOCS 1、SOCS 3或CIS mRNA或蛋白在视网膜中几乎检测不到，但它们的表达在炎症过程中被显著诱导。此外，炎症细胞产生的IFNg与胰岛素协同作用，进一步增强视网膜中SOCS 1和SOCS 3的表达，并诱导视网膜中胰岛素对AKT（PKB）活化的抑制。与精氨酸诱导的SOCS（SOCS 1、SOCS 3、CIS）相反，我们发现SOCS 5、SOCS 6和SOCS 7蛋白在视网膜中组成型表达，并且视网膜细胞中内源性SOCS 6水平的耗尽诱导胰岛素诱导的AKT活化的抑制。这些结果表明，炎症分子如IFNg可能通过诱导CIS、SOCS 1或SOCS 3的表达而促进视网膜中的胰岛素抵抗，而组成性SOCS蛋白如SOCS 6可能促进视网膜中的胰岛素信号传导，并且可能具有神经保护功能。