Published online before print April 13, 2007

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(American Journal of Pathology. 2007;170:2149-2158.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.061018

Interleukin-6 Receptor-Mediated Activation of Signal Transducer and Activator of Transcription-3 (STAT3) Promotes Choroidal Neovascularization

Kanako Izumi-Nagai^*, Norihiro Nagai^*, Yoko Ozawa^*, Masahiko Mihara, Yoshiyuki Ohsugi, Toshihide Kurihara^*, Takashi Koto^*, Shingo Satofuka^*, Makoto Inoue, Kazuo Tsubota, Hideyuki Okano, Yuichi Oike^*¶ and Susumu Ishida^*

From the Laboratories of Retinal Cell Biology^* and Vascular Biology and Metabolism,^¶ and the Departments of Ophthalmology and Physiology, Keio University School of Medicine, Tokyo; and Chugai Pharmaceutical Company Limited, Tokyo, Japan

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 IL-6 receptor or genetic ablation of IL-6 led to significant suppression of CNV. CNV generation was accompanied by STAT3 activation in choroidal endothelial cells and macrophages, and IL-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, IL-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 IL-6 receptor-mediated activation of STAT3 inflammatory pathway in CNV generation, suggesting the possibility of IL-6 receptor blockade as a therapeutic strategy to suppress CNV associated with age-related macular degeneration.

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