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Prathiba Jayaguru, Miguel Joaquin, Susanne Mohr; Interleukin-10, a Potent Counter Regulator of the Hyperglycemia-Induced Pro-Inflammatory Interleukin-1 Signaling in Müller Cells. Invest. Ophthalmol. Vis. Sci. 2013;54(15):3691.
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Recently, we have identified autoinflammation as a potential mechanism for sustaining chronic tissue inflammation in diabetes, which, over time leads to cellular damage and death of retinal cells, such as Müller cells. Interleukin-1β (IL-1β) signaling plays a key role in this pro-inflammatory event. How the IL-1 system is controlled and regulated is unknown to date. Interleukin-10 (IL-10) is an anti-inflammatory cytokine with the potential to regulate IL-1 signaling. However, the mechanism of regulation of IL-1β by IL-10 in Müller cells has not yet been explored and is therefore the focus of this project.
Rat retinal Müller cell line (rMC-1) or isolated human Müller cells (hMC) were treated with normal (5mM) or high glucose (25mM) containing media in the presence or absence of recombinant IL-10 for up to 96 hours. Hyperglycemia-induced gene expression patterns of IL-10 were analyzed by Real-Time PCR. Caspase-1 activity was measured using YVAD-AFC, a caspase-1 specific fluorogenic substrate. Cell death was assessed by Trypan Blue exclusion method.
High glucose down regulated IL-10 mRNA levels by 60% in the Müller cells. Recombinant IL-10 treatment (10ng/ml) significantly reduced hyperglycemia-induced cell death by 51±4.5% (rMC-1) and by 67.1±5.5% (hMC) indicating a strong protective effect of IL-10. Previously, we have shown that hyperglycemia-induced cell death in Müller cells is mediated by active caspase-1 and IL-1β. Therefore, we tested the effect of IL-10 on activation of caspase-1. IL-10 reduced high glucose-induced caspase-1 activity from 50.73±5.1 to 41.71±1.2 pmol AFC/mg/min (normal: 38.51±1.4 pmol AFC/mg/min). Similar results were observed in hMC cells suggesting that IL-10 exerts its protective effect by preventing caspase-1 activation.
IL-10 is a potent counter regulator of high glucose-mediated pro-inflammatory signaling in the Müller cells, shifting the balance towards an anti-inflammatory environment and subsequently protecting cells from cellular damage. Therefore, drugs that target improvement of IL-10 production and signaling might present a new strategy to prevent diabetes-induced damage of retinal cell.
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