Abstract
The autoimmune-mediated beta-cell death in type 1 diabetes (T1DM) is associated with local inflammation (insulitis). We examined the role of MCPIP1 (monocyte chemotactic protein–induced protein 1), a novel cytokine-induced antiinflammatory protein, in this process. Basal MCPIP1 expression was lower in rat vs. human islets and beta-cells. Proinflammatory cytokines stimulated MCPIP1 expression in rat and human islets and in insulin-secreting cells. Moderate overexpression of MCPIP1 protected insulin-secreting INS1E cells against cytokine toxicity by a mechanism dependent on the presence of the PIN/DUB domain in MCPIP1. It also reduced cytokine-induced Chop and C/ebpβ expression and maintained MCL-1 expression. The shRNA-mediated suppression of MCPIP1 led to the potentiation of cytokine-mediated NFκB activation and cytokine toxicity in human EndoC-βH1 beta-cells. MCPIP1 expression was very high in infiltrated beta-cells before and after diabetes manifestation in the LEW.1AR1-iddm rat model of human T1DM. The extremely high expression of MCPIP1 in clonal beta-cells was associated with a failure of the regulatory feedback-loop mechanism, ER stress induction and high cytokine toxicity. In conclusion, our data indicate that the expression level of MCPIP1 affects the susceptibility of insulin-secreting cells to cytokines and regulates the mechanism of beta-cell death in T1DM.
Highlights
Introduction Type1 diabetes (T1DM) is an autoimmune disease characterized by a selective death of pancreatic beta-cells, mediated by an inflammatory process in the pancreatic islets[1,2,3,4]
The Mcpip[1] expression in rat insulin-secreting INS1E cells and in rat islets, as well as in brain was in the range of one third to half of that found in liver, respectively
In the human EndoC-βH1 beta-cells the basal expression was around 2.3-times higher than in rat insulin-secreting INS1E cells as revealed by comparison of the number of copies of MCPIP1 normalized to the number of copies of the house-keeping gene β-actin (INS1E cells: 0.0005 vs. EndoC-βH1 beta-cells: 0.0013, n = 4)
Summary
Introduction Type1 diabetes (T1DM) is an autoimmune disease characterized by a selective death of pancreatic beta-cells, mediated by an inflammatory process in the pancreatic islets (insulitis)[1,2,3,4]. Beta-cell destruction is mediated by CD8+ T cell killing[5] and by the action of proinflammatory cytokines[1,2,6,7]. Proinflammatory cytokines released by activated immune cells infiltrating the islets activate various signaling pathways in beta-cells[1,2,6,7] and can lead to an increase in MHC class I on the surface of beta-cells[8]. The typically secreted cytokines IL-1β, TNFα and IFNγ influence transcription, translation and cause posttranscriptional and posttranslational modifications. These changes eventually lead to nitrooxidative stress and MCPIP1 (monocyte chemotactic protein–induced protein 1) is a novel antiinflammatory protein, discovered in human blood monocytes stimulated with MCP-116 and in human monocyte-derived macrophages stimulated in vivo with IL-1β17. MCPIP1 possesses a PIN-like domain with RNase and deubiquitinase properties
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