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Y. Ito, S. Nakao, Y. Morizane, H. Tanihara, A. Hafezi-Moghadam, J. W. Miller, E. S. Gragoudas, I. K. Kim; Angiopoietin-Like Protein 4 Suppresses Inflammation in Endotoxin-Induced Uveitis. Invest. Ophthalmol. Vis. Sci. 2009;50(13):6039.
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Angiopoietin-like proteins 4 (Angptl4) is a downstream target of the peroxisome proliferators-activated receptors alfa (PPAR) and gamma (PPARγ), which regulate angiogenesis, metabolism, and inflammation. Previously, we reported that Angptl4 suppressed tumor necrosis factor alpha (TNF-) stimulated monocytes adhesion to endothelial cells by modulation of NFΚB signaling in vitro. In this study, we investigate the effect of Angptl4 in endotoxin-induced uveitis (EIU).
EIU was induced in C57BL6 mice by an intraperitoneal injection of lipopolysaccharide (LPS). We examined the time course of expression of Angptl4 in EIU retina by Western blotting analysis. Next, mice were treated with Angptl4 or vehicle before the injection of LPS. The effects of Angptl4 treatment on ocular inflammation were evaluated 24 hours after LPS injection. Aqueous humor was collected by anterior chamber puncture. Protein concentration was determined with a protein quantification kit. For evaluation of inflammatory cells in the anterior chamber, 1 µL of aqueous-humor samples were dropped on a slide, dried and stained. The total number of cells in each drop was counted. Mouse retinas were carefully isolated and placed into 200 µL of lysis buffer supplemented with protease inhibitors and sonicated. Intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and IL-6 levels in mouse retina were determined with the mouse enzyme-linked immunosorbent assay (ELISA) kit. The tissue sample concentration was calculated from a standard curve and corrected for protein concentration. The retina-adherent leukocytes were evaluated by perfusion with fluorescein-isothiocyanate (FITC)-conjugated concanavalin A lectin.
The expression of Angptl4 in retina reduced in EIU. Angptl4 suppressed protein concentration and inflammatory cells in the anterior chamber and suppressed ICAM-1, VCAM-1, and IL-6 protein levels in retina compared to PBS treatment in EIU. Angptl4 suppressed leukocyte adhesion in the EIU retina compared with vehicle-treated.
Inflammatory cytokines such as ICAM-1, VCAM-1, and IL-6 may play an important role in the pathophysiology of ocular inflammatory disease. Our data suggest that Angptl4 suppresses the expression of inflammatory cytokines. Therefore, Angptl4 represents an endogenously expressed protein that may have potential as a therapeutic agent for ocular inflammation.
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