Abstract
The acute-phase response is an inflammatory process triggered mainly by the cytokine IL-6. Signaling of IL-6 is transduced by activation of STAT3 (signal transducer and activator of transcription 3), which rapidly induces the production of acute-phase proteins such as haptoglobin and fibrinogen. Another target of the IL-6/STAT3 signal transduction pathway is the microRNA cluster miR-17/92. Here, we investigated the interplay of miR-17/92 and STAT3 signaling and its impact on the acute-phase response in primary human hepatocytes and hepatoma (HepG2) cells. Employing a reporter gene system consisting of STAT3-sensitive promoter sequences, we show that the miR-17/92 cluster member miR-18a enhanced the transcriptional activity of STAT3. IL-6 stimulation experiments in miR-18a-overexpressing hepatocytes and HepG2 cells revealed an augmented acute-phase response indicated by increased expression and secretion of haptoglobin and fibrinogen. This effect was due, at least in part, to repression of PIAS3 (protein inhibitor of activated STAT, 3), a repressor of STAT3 activity, which we identified as a novel direct target of miR-18a. Finally, we demonstrate that the expression of miR-17/92 in primary hepatocytes and HepG2 cells is modulated by IL-6. Our data reveal, for the first time, a microRNA-mediated positive feedback loop of IL-6 signal transduction leading to an enhanced acute-phase response in human hepatocytes.
Highlights
During inflammation, the production of plasma proteins by hepatocytes is altered either by increasing the levels of plasma proteins or by decreasing their levels
The importance of miRNAs in the signal transduction of IL-6 has been highlighted by a recent study showing that miRNAs derived from the miRNA cluster miR-17/92 modulate STAT3 phosphorylation in multiple myeloma cells (8); Fort et al (9) identified several miRNAs that are directly involved in the production of the acute-phase protein fibrinogen in human hepatoma (HuH-7) cells
We found that IL-6 stimulated the expression of the miRNA cluster miR-17/92 in HepG2 cells and primary hepatocytes, representing a novel positive feedback loop of IL-6 signaling through the repression of the STAT3 inhibitor PIAS3
Summary
Haptoglobin; FGG, fibrinogen ␥-chain; miRNA, microRNA. miR-17/92 Signaling in Acute-phase Response in IL-6 signal transduction contributing to the regulation of the acute-phase response in hepatocytes. MiR-17/92 Signaling in Acute-phase Response in IL-6 signal transduction contributing to the regulation of the acute-phase response in hepatocytes. Because hepatocellular carcinoma (HepG2) cells have been extensively used to investigate the IL-6-induced expression of acute-phase proteins and provide an established model to study the acute-phase response (13), we used these cells in this study to address the role of miR-17/92 in the expression of acute-phase genes and to identify novel miR-17/92 targets in the IL-6 signaling cascade. The interaction between miR-17/92 and the acute-phase response was investigated in primary human hepatocytes to underscore the role of these miRNAs in a physiological setting. For the first time, a miRNA-mediated positive feedback loop of IL-6 signal transduction leading to an enhanced acute-phase response in human hepatocytes
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