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K. Trueblood Doreian, S. Mohr; High Glucose-Induced Caspase-1 Activation in Retinal Müller Cells Is Dependent on Interleukin-1β Signaling. Invest. Ophthalmol. Vis. Sci. 2009;50(13):5369.
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Hyperglycemia leads to sustained activation of caspase-1 in the retina of diabetic animals and patients in vivo and in retinal Müller cells in vitro. How sustained caspase-1 activation is achieved is unknown. Therefore, this study was focused on identifying a potential high glucose-induced autocrine feed-back mechanism responsible for sustained caspase-1 activity in vitro and in vivo.
Transformed rat (rMC-1) and isolated human (hMC) Müller cells were treated in 5mM glucose, 25mM glucose, or 5mM glucose plus IL-1β (2ng/ml) medium for up to 96 hours. Drug wash-out studies were done by incubating rMC-1 in 25mM glucose medium plus YVAD-fmk (100µM), IL-1ra (2ng/ml), or minocycline (100µM.). At 24 hours, treatment medium was washed-out and replaced with high glucose media alone for up to 96 hours. Caspase-1 activity and trypan blue viability assays were performed. In vivo, caspase-1 activity was measured from retinas of normal and diabetic wild type mice (C57Bl6) and mice lacking a functional IL-1β receptor (IL1R-/-).
High glucose induced a bi-phasic pattern of caspase-1 activation in rMC-1 and hMC with peaks at 12-24 and 60-72 hours compared to controls. Blocking high glucose-induced caspase-1/IL-1β signaling during the first phase using the specific caspase-1 inhibitor YVAD-fmk, the IL-1 receptor antagonist IL-1ra, and minocycline, an antibiotic, prevented the second phase of caspase-1 activation and ameliorated Müller cell death. IL-1β itself induced caspase-1 activity within 24 hours. At 10 weeks of diabetes, diabetes significantly increased caspase-1 activity in retinas of wild type and IL1R-/- mice by 1.6 ± 0.2 and 1.3 ± 0.1 fold, respectively. In contrast, at 20 weeks of diabetes caspase-1 activity was only detectable in retinas of diabetic wild type mice but not in the retinas of diabetic IL-1R-/- mice.
These results indicate that sustained caspase-1 activation in hyperglycemic conditions is dependent on functional IL-1ß signaling. Interfering in the caspase-1/IL-1β activation cycle could represent a therapeutic strategy to prevent the progression of diabetic retinopathy.
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