Li Rong, Maminishkis Arvydas, Banzon Tina, Wan Qin, Jalickee Stephen, Chen Shan, Miller Sheldon S
NIH, Bethesda, MD 20892-2510, USA.
Am J Physiol Cell Physiol. 2009 Dec;297(6):C1452-65. doi: 10.1152/ajpcell.00255.2009. Epub 2009 Sep 30.
The present experiments show that IFNgamma receptors are mainly localized to the basolateral membrane of human retinal pigment epithelium (RPE). Activation of these receptors in primary cultures of human fetal RPE inhibited cell proliferation and migration, decreased RPE mitochondrial membrane potential, altered transepithelial potential and resistance, and significantly increased transepithelial fluid absorption. These effects are mediated through JAK-STAT and p38 MAPK signaling pathways. Second messenger signaling through cAMP-PKA pathway- and interferon regulatory factor-1-dependent production of nitric oxide/cGMP stimulated the CFTR at the basolateral membrane and increased transepithelial fluid absorption. In vivo experiments using a rat model of retinal reattachment showed that IFNgamma applied to the anterior surface of the eye can remove extra fluid deposited in the extracellular or subretinal space between the retinal photoreceptors and RPE. Removal of this extra fluid was blocked by a combination of PKA and JAK-STAT pathway inhibitors injected into the subretinal space. These results demonstrate a protective role for IFNgamma in regulating retinal hydration across the outer blood-retinal barrier in inflammatory disease processes and provide the basis for possible therapeutic interventions.
目前的实验表明，γ干扰素受体主要定位于人视网膜色素上皮（RPE）的基底外侧膜。在人胎儿RPE原代培养物中激活这些受体可抑制细胞增殖和迁移，降低RPE线粒体膜电位，改变跨上皮电位和电阻，并显著增加跨上皮液体吸收。这些效应是通过JAK-STAT和p38丝裂原活化蛋白激酶（MAPK）信号通路介导的。通过环磷酸腺苷-蛋白激酶A（cAMP-PKA）信号通路的第二信使信号以及依赖干扰素调节因子-1产生的一氧化氮/环磷酸鸟苷（cGMP）刺激了基底外侧膜上的囊性纤维化跨膜传导调节因子（CFTR），并增加了跨上皮液体吸收。使用视网膜复位大鼠模型进行的体内实验表明，将γ干扰素应用于眼的前表面可清除沉积在视网膜光感受器和RPE之间的细胞外或视网膜下间隙中的多余液体。注入视网膜下间隙的PKA和JAK-STAT通路抑制剂的组合可阻断这种多余液体的清除。这些结果证明了γ干扰素在炎症性疾病过程中调节跨外血视网膜屏障的视网膜水合作用中的保护作用，并为可能的治疗干预提供了依据。
