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A more recent version of this article appeared on June 1, 2007

Published online before print April 13, 2007
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Copyright © 2007 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2007.061018


Article

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

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

From the Laboratories of Retinal Cell Biology* and Vascular Biology and Metabolism, and the Departments of Ophthalmology{dagger} and Physiology,{ddagger} Keio University School of Medicine, Tokyo; and Chugai Pharmaceutical Company Limited,{sect} Tokyo, Japan

@ To whom correspondence should be addressed. E-mail: ishidasu{at}sc.itc.keio.ac.jp.


  Abstract

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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Copyright © 2007 by the American Society for Investigative Pathology.