Elner V M, Elner S G, Standiford T J, Lukacs N W, Strieter R M, Kunkel S L
Department of Ophthalmology, University of Michigan, Ann Arbor 48105, USA.
Exp Eye Res. 1996 Sep;63(3):297-303. doi: 10.1006/exer.1996.0118.
The neuroectodermally-derived retinal pigment epithelium (RPE) forms part of the blood-retina barrier where it is strategically-positioned to regulate leukocyte infiltration in retinal diseases. Activated human RPE cells possess several functions enabling them to perform this role including expression of HLA-DR antigens, production of intercellular adhesion molecule-1, and secretion of monocyte chemotactic protein-1 and interleukin-8. In this study, we examined the ability of interleukin-7 to induce RPE-derived monocyte chemotactic protein-1 and interleukin-8 and assessed the potentiating effects of interleukin-7 on interleukin-1 beta- and tumor necrosis factor-alpha-induced RPE monocyte chemotactic protein-1 and interleukin-8 production. Human RPE cells incubated with interleukin-7 (1-100 ng ml-1) for 24 hr secreted significant levels of antigenic RPE monocyte chemotactic protein-1 and interleukin-8 in a dose-dependent fashion interleukin-7 (P < 0.05). RPE costimulation with interleukin-7 and interleukin-1 beta (2 ng ml-1) or tumor necrosis factor-alpha (2 ng ml-1) resulted in additive increases (P < 0.05) in secreted monocyte chemotactic protein-1 and interleukin-8. Steady-state RPE monocyte chemotactic protein-1 mRNA was substantially increased by interleukin-7 (1-100 ng ml-1), while RPE interleukin-8 mRNA was mildly elevated by higher doses of interleukin-7 (10-100 ng ml-1). Time-dependent increases in RPE monocyte chemotactic protein-1 and interleukin-8 mRNA were noted. RPE monocyte chemotactic protein-1 mRNA peaked at 2 hr and decreased over 8 hr and 24 hr. Whereas, RPE interleukin-8 mRNA was perceptible at 2 hr, maximal at 8 hr, and reduced by 24 hr. Interleukin-7 potentiated interleukin-1 beta-induced monocyte chemotactic protein-1 and interleukin-8 steady-state mRNA expression at all interleukin-7 concentrations. Interleukin-7 potentiated tumor necrosis factor-alpha-induced RPE monocyte chemotactic protein-1 steady-state mRNA expression at all doses of interleukin-7 while only high dose interleukin-7 (100 ng ml-1) enhanced tumor necrosis factor-alpha-induced RPE interleukin-8 steady-state gene expression. Our data show that interleukin-7 is a primary stimulus of RPE monocyte chemotactic protein-1 and interleukin-8. This is one of the first reports demonstrating: (1) interleukin-7 induction of monocyte chemotactic protein-1 in any cell type, and (2) interleukin-7 induction of interleukin-8 in resident, tissue-based cells. These studies suggest that interleukin-7 potentiation of interleukin-1 beta and tumor necrosis factor-alpha-induced RPE monocyte chemotactic protein-1 and IL-8 may be important for the elicitation of leukocyte chemotaxins in diseased retinal tissue when only low ambient levels of individual pro-inflammatory cytokines are present.
神经外胚层来源的视网膜色素上皮（RPE）构成血视网膜屏障的一部分，其位置关键，可调节视网膜疾病中的白细胞浸润。活化的人RPE细胞具有多种功能，使其能够发挥这一作用，包括HLA-DR抗原的表达、细胞间黏附分子-1的产生以及单核细胞趋化蛋白-1和白细胞介素-8的分泌。在本研究中，我们检测了白细胞介素-7诱导RPE来源的单核细胞趋化蛋白-1和白细胞介素-8的能力，并评估了白细胞介素-7对白细胞介素-1β和肿瘤坏死因子-α诱导的RPE单核细胞趋化蛋白-1和白细胞介素-8产生的增强作用。用白细胞介素-7（1 - 100 ng/ml）孵育人RPE细胞24小时，以剂量依赖方式分泌了显著水平的抗原性RPE单核细胞趋化蛋白-1和白细胞介素-8（P < 0.05）。白细胞介素-7与白细胞介素-1β（2 ng/ml）或肿瘤坏死因子-α（2 ng/ml）共同刺激RPE，导致分泌的单核细胞趋化蛋白-1和白细胞介素-8呈相加性增加（P < 0.05）。白细胞介素-7（1 - 100 ng/ml）使RPE单核细胞趋化蛋白-1的稳态mRNA显著增加，而较高剂量的白细胞介素-7（10 - 100 ng/ml）使RPE白细胞介素-8的mRNA轻度升高。观察到RPE单核细胞趋化蛋白-1和白细胞介素-8 mRNA随时间的增加。RPE单核细胞趋化蛋白-1 mRNA在2小时达到峰值，并在8小时和24小时下降。而RPE白细胞介素-8 mRNA在2小时可检测到，8小时达到最大值，并在24小时降低。在所有白细胞介素-7浓度下，白细胞介素-7均增强白细胞介素-1β诱导的单核细胞趋化蛋白-1和白细胞介素-8稳态mRNA表达。在所有白细胞介素-7剂量下，白细胞介素-7均增强肿瘤坏死因子-α诱导的RPE单核细胞趋化蛋白-1稳态mRNA表达，而只有高剂量的白细胞介素-7（100 ng/ml）增强肿瘤坏死因子-α诱导的RPE白细胞介素-8稳态基因表达。我们的数据表明，白细胞介素-7是RPE单核细胞趋化蛋白-1和白细胞介素-8的主要刺激物。这是首批证明以下两点的报告之一：（1）白细胞介素-7在任何细胞类型中诱导单核细胞趋化蛋白-1，以及（2）白细胞介素-7在驻留的组织细胞中诱导白细胞介素-8。这些研究表明，当疾病视网膜组织中仅存在低水平的单个促炎细胞因子时，白细胞介素-7增强白细胞介素-1β和肿瘤坏死因子-α诱导的RPE单核细胞趋化蛋白-1和白细胞介素-8可能对白细胞趋化因子的引发很重要。
