Interleukin-6 receptor-mediated activation of signal transducer and activator of transcription-3 (STAT3) promotes choroidal neovascularization.

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.

• Authors: 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, Susumu Ishida
• Journal: The American journal of pathology (Am J Pathol) Vol. 170 Issue 6 Pg. 2149-58 (Jun 2007) ISSN: 0002-9440 [Print] United States
• PMID: 17525280 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin-6
• Receptors, Interleukin-6
• STAT3 Transcription Factor
• Stat3 protein, mouse
• Extracellular Signal-Regulated MAP Kinases

Topics

• Animals
• Choroidal Neovascularization
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Humans
• Inflammation (metabolism)
• Interleukin-6 (metabolism)
• Macrophages (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Phosphorylation
• Receptors, Interleukin-6 (antagonists & inhibitors, genetics, metabolism)
• STAT3 Transcription Factor (genetics, metabolism)
• Signal Transduction (physiology)