期刊
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
卷 50, 期 4, 页码 1920-1928出版社
ASSOC RESEARCH VISION OPHTHALMOLOGY INC
DOI: 10.1167/iovs.08-2082
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资金
- National Institutes of Health Training [2T32EY007157, 1F31EY018075, EY-014380, EY-017206, DK-065014, EY-016077]
- Visual Science Research Center Core [2P30EY011373]
- American Diabetes Association [7-06-RA-95]
- Juvenile Diabetes Research Foundation International [2-2005-97]
- NATIONAL EYE INSTITUTE [F31EY018075, P30EY011373, R03EY014380, T32EY007157, R01EY016077, R01EY017206] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R21DK065014] Funding Source: NIH RePORTER
PURPOSE. This study determined the role of the proinflammatory cytokines known to be elevated in the diabetic retina, namely IL-1 beta, TNF alpha, and IL-6, in a high glucose-induced nuclear accumulation of GAPDH in retinal Muller cells, an event considered crucial for the induction of cell death. METHODS. With use of the transformed rat Muller cell line (rMC-1) and isolated human Muller cells (HMCs), the authors examined the effect of high glucose (25 mM), IL-1 beta, TNF alpha, IL-6, and high glucose (25 mM) plus inhibitors of the caspase1/IL-1 beta signaling pathway on GAPDH nuclear accumulation, which was evaluated by immunofluorescence analysis. RESULTS. High glucose induced IL-1 beta, weak IL-6, and no TNF alpha production by rMC-1 and HMCs. IL-1 beta (1-10 ng/mL) significantly increased GAPDH nuclear accumulation in Muller cells in a concentration-dependent manner within 24 hours. Further, high glucose-induced GAPDH nuclear accumulation in Muller cells was mediated by IL-1 beta. Inhibition of the IL-1 receptor using an IL-1 receptor antagonist (IL-1ra; 50 ng/mL) or inhibition of IL-1 beta production using a specific caspase-1 inhibitor (YVAD-fmk; 100 mu M) significantly decreased high glucose-induced GAPDH nuclear accumulation. In contrast, IL-6 (2 ng/mL) had a strong protective effect attenuating high glucose and IL-1 beta-induced GAPDH nuclear accumulation in Muller cells. TNF alpha (1-10 ng/mL) did not have any effect on GAPDH nuclear accumulation. CONCLUSIONS. These results revealed a novel mechanism for high glucose-induced GAPDH nuclear accumulation in Muller cells through production and autocrine stimulation by IL-1 beta. The protective role of IL-6 in high glucose- and IL-1 beta-induced toxicity indicates that changes in the balance of these cytokines might contribute to cellular damage mediated by elevated glucose levels. (Invest Ophthalmol Vis Sci. 2009; 50: 1920-1928) DOI: 10.1167/iovs.08-2082
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