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D. Reis, J. Simon, P. G. Mascaro, J. Pearsall, J. C. Blanks, Y. Shibata, C. K. Dorey; IL-10 Inhibits Early Events in Angiogenesis. Invest. Ophthalmol. Vis. Sci. 2009;50(13):5690.
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In the murine model of oxygen-induced retinopathy (OIR), we previously reported that intravitreal IL-10, administered on P12 as mice were transferred to room air, caused strong selective inhibition of neovascularization (NV) at P17 without an effect on intraretinal angiogenesis. Because IL-10 has a short half-life, we hypothesized that the IL-10 effects were mediated by its well-known suppression of macrophage (MΦ) recruitment and expression of inflammatory cytokines (e.g. IL-1, IL-6, TNF, and MCP-1), and further, that these cytokines contribute to early pathological NV. However, others have reported that higher doses of IL-10 stimulate NV in the OIR model. To better understand the effect of IL-10 on early events in angiogenesis, we examined VEGF-dependent microvessel formation in aortic rings, in which early angiogenesis is enhanced by MΦ cytokines (Gelati et al, 2008).
Aortic rings were prepared from the ascending aorta of ~2 month old mice and fed every 48 hrs with control media (MCDB131 + 20 ng VEGF/ml +2.5% FBS) or control media + IL-10 (25, 50, 125, 250, 500 or 2000 ng/ml). Microvessels were counted at day 7 or 10. IL-10 signal transduction is mediated by heme oxygenase (HO-1)-dependent generation of carbon monoxide, which has both proangiogenic and anti-inflammatory effects. Therefore, we also examined the effect of an HO-1 substrate (2.5 µM hemin) on the IL-10 response. Statistical comparisons were made with Student's t-tests.
Angiogenesis was inhibited 25% (P=0.1) at 2 µg IL-10/ml (approximately equal to intravitreal injection of 10 ng IL-10). However, IL-10 at 25-500 ng/ml had no significant effect on microvessel formation. Hemin alone had no effect on angiogenesis, but hemin plus 50 ng IL-10 /ml caused 50% inhibition (P<0.01).
IL-10 significantly inhibits early events in inflammatory-mediated angiogenesis, and this response is dependent on heme-oxygenase activity. The failure to detect a proangiogenic effect of IL-10 may relate to the concurrent exposure to VEGF in both the aortic ring assay, and in the retina in the OIR model. These results suggest that the role of IL-10 in the OIR model deserves further study.
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