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Differential Regulation of High Glucose–Induced Glyceraldehyde-3-Phosphate Dehydrogenase Nuclear Accumulation in Müller Cells by IL-1β and IL-6

¹From the Departments of Physiology and Biophysics, ²Medicine, and ⁵Ophthalmology, Case Western Reserve University, School of Medicine, Cleveland, Ohio; the ³Department of Ophthalmology, Northwestern University, Chicago, Illinois; and the ⁴Department of Physiology, Michigan State University, East Lansing, Michigan.

PURPOSE. This study determined the role of the proinflammatory cytokines known to be elevated in the diabetic retina, namely IL-1β, TNF, and IL-6, in a high glucose–induced nuclear accumulation of GAPDH in retinal Müller cells, an event considered crucial for the induction of cell death.

METHODS. With use of the transformed rat Müller cell line (rMC-1) and isolated human Müller cells (HMCs), the authors examined the effect of high glucose (25 mM), IL-1β, TNF, IL-6, and high glucose (25 mM) plus inhibitors of the caspase-1/IL-1β signaling pathway on GAPDH nuclear accumulation, which was evaluated by immunofluorescence analysis.

RESULTS. High glucose induced IL-1β, weak IL-6, and no TNF production by rMC-1 and HMCs. IL-1β (1–10 ng/mL) significantly increased GAPDH nuclear accumulation in Müller cells in a concentration-dependent manner within 24 hours. Further, high glucose–induced GAPDH nuclear accumulation in Müller cells was mediated by IL-1β. Inhibition of the IL-1 receptor using an IL-1 receptor antagonist (IL-1ra; 50 ng/mL) or inhibition of IL-1β production using a specific caspase-1 inhibitor (YVAD-fmk; 100 µM) 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-1β–induced GAPDH nuclear accumulation in Müller cells. TNF (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 Müller cells through production and autocrine stimulation by IL-1β. The protective role of IL-6 in high glucose– and IL-1β–induced toxicity indicates that changes in the balance of these cytokines might contribute to cellular damage mediated by elevated glucose levels.

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