Interleukin-6 receptor-mediated activation of signal transducer and activator of transcription-3 (STAT3) promotes choroidal neovascularization
Interleukin-6 receptor-mediated activation of signal transducer and activator of transcription-3 (STAT3) promotes choroidal neovascularization
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DOI：
10.2353/ajpath.2007.061018
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发表时间：
2007-06-01
影响因子：
6
通讯作者：
Ishida, Susumu
中科院分区：
文献类型：
--
作者：
Izumi-Nagai, Kanako;Nagai, Norihiro;Ishida, Susumu
白细胞介素 (IL)-6 是一种强效促炎细胞因子，被认为是脉络膜新生血管 (CNV) 的危险因素，因为其在年龄相关性黄斑变性患者血清中的水平升高；然而，IL-6 在 CNV 中的作用尚未明确。本研究揭示了 IL-6 信号传导及其下游 STAT3 通路对激光诱导 CNV 小鼠模型的关键贡献。激光治疗诱导的 CNV 刺激了视网膜色素上皮-脉络膜复合体中 IL-6 的表达，基于抗体的 M-6 受体阻断或 M-6 的基因消融导致 CNV 的显着抑制。 CNV 的产生伴随着脉络膜内皮细胞和巨噬细胞中 STAT3 的激活，M-6 受体阻断导致选择性抑制 STAT3 的磷酸化，但不抑制细胞外信号调节激酶 1/2。一致地，药物阻断 STAT3 通路也抑制 CNV。此外，M-6受体中和导致体内和体外炎症相关分子（包括单核细胞趋化蛋白、细胞间粘附分子-1和血管内皮生长因子）的表达以及巨噬细胞浸润CNV的显着抑制。这些结果表明 H,6 受体介导的 STAT3 炎症通路激活在 CNV 生成中显着参与，表明 M-6 受体阻断作为抑制与年龄相关性黄斑变性相关的 CNV 的治疗策略的可能性。
Interleukin (IL)-6, a potent proinflammatory cytokine, is suggested to be a risk factor for choroidal neovascularization (CNV) because of its increased levels in the serum of patients with age-related macular degeneration; however, the role of IL-6 in CNV has not been defined. The present study reveals the critical contribution of IL-6 signaling and its downstream STAT3 pathway to the murine model of laser-induced CNV. CNV induction by laser treatment stimulated IL-6 expression in the retinal pigment epithelium-choroid complex, and antibody-based blockade of M-6 receptor or genetic ablation of M-6 led to significant suppression of CNV. CNV generation was accompanied by STAT3 activation in choroidal endothelial cells and macrophages, and M-6 receptor blockade resulted in selectively inhibited phosphorylation of STAT3 but not extracellular signal-regulated kinase 1/2. Consistently, pharmacological blockade of STAT3 pathway also suppressed CNV. in addition, M-6 receptor neutralization led to significant inhibition of the in vivo and in vitro expression of inflammation-related molecules including monocyte chemotactic protein, intercellular adhesion molecule-1, and vascular endothelial growth factor, and of macrophage infiltration into CNV. These results indicate the significant involvement of H,6 receptor-mediated activation of STAT3 inflammatory pathway in CNV generation, suggesting the possibility of M-6 receptor blockade as a therapeutic strategy to suppress CNV associated with age-related macular degeneration.