Ebong Samuel, Yu Cheng-Rong, Carper Deborah A, Chepelinsky Ana B, Egwuagu Charles E
Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Invest Ophthalmol Vis Sci. 2004 Mar;45(3):872-8. doi: 10.1167/iovs.03-0311.
This study was conducted to examine whether the effects of growth factors are mediated in the lens by Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathways and whether they induce expression of suppressors of cytokine signaling (SOCS), a novel family of feedback regulators of cytokine and growth factor activities.
STAT activation and SOCS expression were analyzed in transgenic or wild-type mouse lens and lens epithelial cells stimulated with growth factors by immunohistochemistry, RT-PCR, Northern, Western, proliferation, or transient reporter assays.
STATs were constitutively expressed at low levels and activated by insulin-like growth factor (IGF)-1, platelet-derived growth factor (PDGF)-aa, and FGF-1 or -2 in the lens. The Intensity of STAT signaling increased at high FGF-2 concentration and FGFs act in synergy with IGF-1 or PDGFaa to enhance STAT signaling and SOCS expression. Growth factor-induced proliferation of lens cells is inhibited by AG-490, a specific inhibitor of JAK2/STAT3.
This is the first report that FGFs activate STAT pathways in the lens and that SOCS proteins are constitutively expressed and upregulated by growth factors in this tissue. Physiological relevance of STAT pathways in the lens is underscored by inhibition of lens cell proliferation by inhibitors of JAK/STAT pathways and by the aberrant proliferation of lens epithelium in the posterior pole of transgenic mice with constitutively activated STAT1 in the lens. Common activation of STAT pathways by FGF-1, FGF-2, IGF-1, or PDGFaa and their synergistic activation of STATs and SOCS in lens cells suggest that activities and crosstalk between these factors are sensitive to the steady state levels of activated STATs in the lens and may be under feedback regulation by SOCS family proteins.
本研究旨在探讨生长因子的作用是否通过Janus激酶/信号转导子和转录激活子（JAK/STAT）途径在晶状体中介导，以及它们是否诱导细胞因子信号转导抑制因子（SOCS）的表达，SOCS是细胞因子和生长因子活性的新型反馈调节因子家族。
通过免疫组织化学、RT-PCR、Northern、Western、增殖或瞬时报告基因检测，分析转基因或野生型小鼠晶状体及晶状体上皮细胞在生长因子刺激下的STAT激活和SOCS表达。
STATs在晶状体中以低水平组成性表达，并被胰岛素样生长因子（IGF）-1、血小板衍生生长因子（PDGF）-aa以及FGF-1或FGF-2激活。在高浓度FGF-2时，STAT信号强度增加，且FGFs与IGF-1或PDGFaa协同作用以增强STAT信号和SOCS表达。AG-490（一种JAK2/STAT3的特异性抑制剂）可抑制生长因子诱导的晶状体细胞增殖。
这是首篇报道FGFs在晶状体中激活STAT途径，以及SOCS蛋白在该组织中组成性表达并被生长因子上调的研究。JAK/STAT途径抑制剂对晶状体细胞增殖的抑制以及晶状体中STAT1组成性激活的转基因小鼠后极部晶状体上皮细胞的异常增殖，突显了晶状体中STAT途径的生理相关性。FGF-1、FGF-2、IGF-1或PDGFaa对STAT途径的共同激活以及它们在晶状体细胞中对STATs和SOCS的协同激活表明，这些因子之间的活性和相互作用对晶状体中激活的STATs的稳态水平敏感，且可能受SOCS家族蛋白的反馈调节。
