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, Susumu Ishida

Research output: Contribution to journalArticle

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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 EL-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.

Original languageEnglish
Pages (from-to)2149-2158
Number of pages10
JournalAmerican Journal of Pathology
Volume170
Issue number6
DOIs
Publication statusPublished - 2007 Jun

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Interleukin-6 Receptors
STAT3 Transcription Factor
Choroidal Neovascularization
Interleukin-6
Macular Degeneration
Monocyte Chemoattractant Proteins
Lasers
Macrophages
Mitogen-Activated Protein Kinase 3
Choroid
Retinal Pigment Epithelium
Mitogen-Activated Protein Kinase 1
Intercellular Adhesion Molecule-1
Vascular Endothelial Growth Factor A
Transcriptional Activation
Endothelial Cells
Phosphorylation
Pharmacology
Cytokines
Inflammation

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Interleukin-6 receptor-mediated activation of signal transducer and activator of transcription-3 (STAT3) promotes choroidal neovascularization. / Izumi-Nagai, Kanako; Nagai, Norihiro; Ozawa, Yoko; Mihara, Masahiko; Ohsugi, Yoshiyuki; Kurihara, Toshihide; Koto, Takashi; Satofuka, Shingo; Inoue, Makoto; Tsubota, Kazuo; Okano, Hideyuki; Oike, Yuichi; Ishida, Susumu.

In: American Journal of Pathology, Vol. 170, No. 6, 06.2007, p. 2149-2158.

Research output: Contribution to journalArticle

Izumi-Nagai, Kanako ; Nagai, Norihiro ; Ozawa, Yoko ; Mihara, Masahiko ; Ohsugi, Yoshiyuki ; Kurihara, Toshihide ; Koto, Takashi ; Satofuka, Shingo ; Inoue, Makoto ; Tsubota, Kazuo ; Okano, Hideyuki ; Oike, Yuichi ; Ishida, Susumu. / Interleukin-6 receptor-mediated activation of signal transducer and activator of transcription-3 (STAT3) promotes choroidal neovascularization. In: American Journal of Pathology. 2007 ; Vol. 170, No. 6. pp. 2149-2158.
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AU - Izumi-Nagai, Kanako

AU - Nagai, Norihiro

AU - Ozawa, Yoko

AU - Mihara, Masahiko

AU - Ohsugi, Yoshiyuki

AU - Kurihara, Toshihide

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AU - Satofuka, Shingo

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AU - Okano, Hideyuki

AU - Oike, Yuichi

AU - Ishida, Susumu

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