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Derrick Feenstra, Prathiba Jayaguru, Charles Dinarello, Susanne Mohr; Impact of Interleukin-1α on Hyperglycemia-Induced Inflammation and Cell Death in Müller Cells. Invest. Ophthalmol. Vis. Sci. 2013;54(15):3243.
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Inflammation mediated by interleukin-1β (IL-1β)/IL-1 receptor plays a key role in the progression of diabetic retinopathy. Müller cells are the main source of IL-1β contributing to retinal inflammation in diabetes. Whereas much is known about the activation of IL-1β signaling, less is known about interleukin-1α (IL-1α), which activates the same IL-1 receptor and possesses the same inflammatory properties as IL 1β. IL-1α can translocate to the nucleus and participates as a transcription factor for pro-inflammatory genes. With cell death, the IL-1α precursor is released and is biologically active. To date there are no reports of hyperglycemia influencing IL-1α localization and function in retinal cells. Thus, the focus of this study was to identify whether hyperglycemia influences IL-1α cellular localization, IL-1β mediated inflammatory signaling, and cell viability in Müller cells.
Müller cells were treated with normal (5mM) or high (25mM) glucose containing medium for 48 or 96 hours. Nuclear localization of IL-1α was determined using immunohistochemistry (IHC) or Western Blot analysis of nuclear fractions. Caspase-1 activity was measured in Müller treated with normal and high glucose medium in the presence or absence of a specific human monoclonal anti-human anti-IL-1α (10μg/ml) after 96 hours of treatment. Cell death was measured using Trypan Blue exclusion method.
Hyperglycemia led to a significant decrease of 24±6% in active IL-1α in the cytosol of Müller. At 48 hours of high glucose treatment, IL-1α was predominantly cytosolic. At 96 hours of high glucose treatment, there was a significant, 3-fold increase in IL-1α levels in the nucleus. Nuclear IL-1α seemed clustered. Western Blot analysis of nuclear fractions confirmed increased nuclear localization of IL-1α at 96 hours. Anti-IL-1α treatment led to an 87±13.5% decrease in caspase activity and 76±14% decrease in cell death in Müller treated with high glucose.
Hyperglycemia alters cellular localization of IL-1α in Müller cells. For the first time, we have shown that under hyperglycemic conditions IL-1α influences activation of caspase-1 and thus the IL-1β pathway indicating that these members of the IL-1 family strongly regulate each other. Identifying the interaction between IL-1 family members is crucial for the understanding of the development of diabetic retinopathy.
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