High Glucose-Induced Glyceraldehyde-3-Phosphate Dehydrogenase Nuclear Accumulation in Mueller Cells is Regulated by Interleukin-1 and Interleukin-6

¹ Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio, United States
² Medicine, Case Western Reserve University, Cleveland, Ohio, United States
³ Ophthalmology, Northwestern University Medical School, Chicago, Illinois, United States
⁴ Michigan State University, East Lansing, Michigan, United States
⁵ Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio, 44106, United States

^* To whom correspondence should be addressed. E-mail: sxm38{at}po.cwru.edu.

	Abstract

Purpose. This study determined the role of pro-inflammatory cytokines known to be elevated in the diabetic retina, namely IL-1, TNF, and IL-6 in high glucose-induced nuclear accumulation of GAPDH in retinal Mueller cells, an event considered crucial for the induction of cell death. Methods. Using transformed rat (rMC-1) and isolated human (HMC) Mueller cells, we examined the effect of high glucose (25 mM), IL-1, TNF, IL-6, and high glucose (25mM) plus inhibitors of the caspase-1/IL-1 signaling pathway on GAPDH nuclear accumulation which was evaluated by immunofluorescence analysis. Results. High glucose induced IL-1, weak IL-6, and no TNF production by rMC-1 and HMC. IL-1 (1-10ng/ml) significantly increased GAPDH nuclear accumulation in Mueller cells in a concentration dependent manner within 24 hours. Further, high glucose-induced GAPDH nuclear accumulation in Mueller cells is mediated by IL-1. Inhibition of the IL-1 receptor using an IL-1 receptor antagonist (IL-1ra, 50ng/ml) or inhibition of IL-1 production using a specific caspase-1 inhibitor (YVAD-fmk, 100µM) significantly decreased high glucose-induced GAPDH nuclear accumulation. In contrast, IL-6 (2ng/ml) had a strong protective effect attenuating high glucose and IL-1-induced GAPDH nuclear accumulation in Mueller cells. TNF (1-10ng/ml) did not have any effect on GAPDH nuclear accumulation. Conclusions. Our results reveal a novel mechanism for high glucose-induced GAPDH nuclear accumulation in Mueller cells through production and autocrine stimulation by IL-1. The protective role of IL-6 in high glucose and IL-1-induced toxicity indicates that changes in the balance of these cytokines might contribute to cellular damage mediated by elevated glucose levels.

Key Words: cytokine, Mueller cell, cell death

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