RORα suppresses interleukin-6-mediated hepatic acute phase response
Acute liver failure (ALF) is characterized by loss of liver function in response to sustained augmentation of the acute-phase response (APR) in the liver, which can progress even to death. Although the inflammatory interleukin-6 (IL-6)-axis is a crucial factor that drives the hepatic APR by releasin...
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Published in | Scientific reports Vol. 9; no. 1; pp. 11798 - 9 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
England
Nature Publishing Group
13.08.2019
Nature Publishing Group UK |
Subjects | |
Online Access | Get full text |
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Summary: | Acute liver failure (ALF) is characterized by loss of liver function in response to sustained augmentation of the acute-phase response (APR) in the liver, which can progress even to death. Although the inflammatory interleukin-6 (IL-6)-axis is a crucial factor that drives the hepatic APR by releasing diverse acute-phase proteins (APPs), therapeutic strategies to block the IL-6-STAT3-mediated APR are not well developed. Here, we show that the nuclear receptor retinoic acid-related orphan receptor α (RORα) limits APR-mediated liver injury by inhibiting the hepatic IL-6-STAT3 signaling pathway. Administration of JC1-40, an RORα activator, diminished diethylnitrosamine-induced acute liver injury and repressed transcriptional expression of APPs such as CXCL1 and LCN2 in mice. IL-6-mediated activation of STAT3 was repressed after RORα activation by either adenoviral infusion of RORα or JC1-40 treatment in primary hepatocytes. Activation of RORα decreased transcriptional expression of IL-6 receptor α, an upstream activator of STAT3, both in vitro and in vivo. This may be one mechanism underlying the RORα-mediated inhibition of STAT3. Taken together, our results suggest that RORα is a regulator of the hepatic IL-6-STAT3 signaling pathway and may be a new therapeutic target for treating APR-associated inflammatory ALF. |
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ISSN: | 2045-2322 2045-2322 |
DOI: | 10.1038/s41598-019-48171-8 |