Abstract
We have previously reported that long-term treatment of beta cells with interleukin-6 (IL-6) is pro-apoptotic. However, little is known about the regulatory mechanisms that are involved. Therefore, we investigated pro-apoptotic changes in mRNA expression in beta cells in response to IL-6 treatment. We analyzed a microarray with RNA from INS-1 beta cells treated with IL-6, and found that TNF-α mRNA was significantly upregulated. Inhibition of TNF-α expression by neutralizing antibodies significantly decreased annexin V staining in cells compared with those treated with a control antibody. We identified three microRNAs that were differentially expressed in INS-1 cells incubated with IL-6. In particular, miR-181c was significantly downregulated in IL-6-treated cells compared with control cells and the decrease of miR-181c was attenuated by STAT-3 signaling inhibition. TNF-α mRNA was a direct target of miR-181c and upregulation of miR-181c by mimics, inhibited IL-6-induced increase in TNF-α mRNA expression. Consequently, reduction of TNF-α mRNA caused by miR-181c mimics enhanced cell viability in IL-6 treated INS-1 cells. These results demonstrated that miR-181c regulation of TNF-α expression plays a role in IL-6-induced beta cell apoptosis.
Highlights
Prolonged and uncontrolled activation of inflammation is a hallmark of many diseases, such as obesity-associated metabolic disorders including type 1 and type 2 diabetes [1]
To identify mRNAs and miRNAs associated with IL-6-induced beta cell apoptosis, we investigated changes in gene expression in IL-6-treated INS-1 cells
We found that tumor necrosis factor (TNF)-α expression was highly upregulated in IL-6-treated INS-1 cells, and that miR-181c contributed to IL-6-induced beta cell apoptosis through regulation of TNF-α expression
Summary
Prolonged and uncontrolled activation of inflammation is a hallmark of many diseases, such as obesity-associated metabolic disorders including type 1 and type 2 diabetes [1]. Overload cells triggers obesity induced inflammation, which is elevated expression of cytokines, chemokines and inflammatory mediators from metabolic organs and results in systemic inflammatory responses and disrupt glucose homeostasis [2]. Interleukin (IL)-6 is a pleiotropic cytokine that is associated with several immunoinflammatory and autoimmune diseases such as systemic lupus erythematous, rheumatoid arthritis and diabetes [3,4,5] and is produced by a variety of different cell types with complex, cell-specific mechanisms [6].
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