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

细胞因子信号转导抑制蛋白家族包含8个成员(SOCS1至SOCS7和细胞因子诱导的SH2蛋白或CIS)，每个成员都含有一个保守的中央Src同源2(SH2)结构域和一个长度可变的N末端结构域和一个40个氨基酸组成的C末端结构域，称为SoCS box。SOCS蛋白通过相关的JAK激酶调节由造血素细胞因子受体传递的信号。胰岛素和其受体具有固有酪氨酸激酶活性的生长因子(IGF-1、FGFs、PDGF、EGF和EPO)诱导的信号也受到SOCS蛋白的反馈调节。人们对SOCS家族的兴趣源于这样一种信念，即SOCS蛋白的功能是整合多种细胞因子/生长因子信号，并介导拮抗因子之间的交叉通讯。由于SOCS基因缺失或SOCS基因表达失调而导致的各种病理情况，突显了SOCS蛋白的重要性。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、肝脏退化、淋巴系统缺陷、多囊肾病和癌症。在这项研究中，我们的重点放在两个方面：(I)SOCS蛋白的潜在神经保护作用。我们检测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基因的瞬时表达，以确定SOCS的表达模式是否与EAU的严重程度或宿主保护机制有关。EAU是一种T细胞介导的疾病，用作人类葡萄膜炎的模型。我们发现，炎症细胞因子诱导的SOCS1和SOCS3蛋白在EAU中通过负向调节IFNG活性而在减轻葡萄膜炎中发挥重要作用，而在视网膜中结构性表达的SOCS5则起到保护作用。这些结果表明，SOCS蛋白可能具有缩短促炎症细胞因子在视网膜中有害活动的持续时间的功能，并增加营养因子的水平，从而提高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，尽管在视网膜中几乎检测不到SOCS1、SOCS3或CIS的mRNAs或蛋白质，但它们在炎症过程中显著诱导表达。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SOCS1和SOCS3的表达，并诱导胰岛素抑制视网膜中AKT(PKB)的激活。与细胞因子诱导的SOCS(SOCS1、SOCS3、CIS)相比，我们发现SOCS5、SOCS6和SOCS7蛋白在视网膜中有结构性表达，视网膜细胞内源性SOCS6水平的降低导致胰岛素诱导的AKT激活受到抑制。这些结果表明，炎症分子如IFNG可能通过诱导CIS、SOCS1或SOCS3的表达来促进视网膜的胰岛素抵抗，而构成SOCS的蛋白如SOCS6可能促进视网膜的胰岛素信号转导，并可能具有神经保护作用。

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.