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Steve Louie, Maura Crowley, Omar Delgado, Natasha Buchanan, Bruce Jaffee, Sha-Mei Liao; Rapamycin Reduces Macrophages While Cyclosporine A Reduces Neutrophils In The Retina In Mouse Endotoxin-induced Uveitis. Invest. Ophthalmol. Vis. Sci. 2011;52(14):1360.
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© ARVO (1962-2015); The Authors (2016-present)
To determine the effects of 2 immunosupressant agents (rapamycin, an inhibitor of the mammalian target of rapamycin complex 1 (mTORC1), and cyclosporine A, a calcineurin and apoptosis inhibitor) on retinal inflammation in a mouse endotoxin (lipopolysaccharide=LPS)-induced uveitis model.
LPS (50 ug) was administered intraperitoneally to 7-week-old C57BL/6 female mice. Rapamycin or cyclosporine A was dosed via oral gavage one hour prior to LPS challenge. Eyes were collected and dissected 3, 8, 16, and 24 hours post LPS administration. Samples were analyzed for cytokines/chemokines and leukocytes. Retinal neutrophils and macrophages/monocytes of retinal flat mounts were detected by immuno-staining with Gr-1 and F4/80, respectively. Fluorescent cells were quantified using Axiovision software.
Increasing doses of rapamycin from 0.3 mg/kg to 10 mg/kg resulted in a dose-dependent reduction of macrophages but not neutrophils in the retina at 24 hours. Rapamycin at 10 mg/kg reduced retinal macrophages/monocytes by 85% (p<0.001). In contrast, cyclosporine A had no significant effect on macrophages but reduced neutrophils by 55% (p<0.01) at 30 mg/kg. Rapamycin markedly inhibited LPS-induced plasma ICAM-1 production by >75% (p<0.001). At 3-8 hours after LPS administration, rapamycin potently blocked Th1-associated cytokines such as IL-12p70, IFN-γ, and IL-2 in the eyes (70-100% reduction, p < 0.01), likely due to the reduction in macrophages. Cyclosporine A, on the other hand, augmented LPS-induced plasma IL-10 (an anti-inflammatory cytokine) level by >4-fold (p<0.01).
Rapamycin specifically inhibits LPS-induced infiltration of macrophages/monocytes but not neutrophils into the mouse retina. Cyclosporine A partially inhibits LPS-induced infiltration of neutrophils. Rapamycin and cyclosporine A also exhibited different effects on cytokines and cell adhesion molecules in response to LPS. Taken together, these results suggest that the two immunosuppressant drugs have distinct effects on LPS-trigged innate immune responses.
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