RORα suppresses interleukin-6-mediated hepatic acute phase response

• Published in: Scientific reports 2019-08, Vol.9 (1), p.11798-9, Article 11798
• Main Authors: Kim, Ju-Yeon, Han, Yong-Hyun, Nam, Min-Woo, Kim, Hyeon-Ji, Lee, Mi-Ock
• Format: Article
• Language: English
• Subjects: 13; 13/51; 45/15; 631/337; 631/337/572; 631/80; 64/60; 82/80; 96/106; Acute phase proteins; Acute-Phase Reaction - genetics; Adenoviridae - genetics; Animals; Chemical and Drug Induced Liver Injury - drug therapy; Chemical and Drug Induced Liver Injury - genetics; Chemical and Drug Induced Liver Injury - pathology; Chemokine CXCL1 - genetics; Cytokines; Deoxyuracil Nucleotides - pharmacology; Diethylnitrosamine; Diethylnitrosamine - toxicity; Disease Models, Animal; Gene Expression Regulation - drug effects; Hepatocytes; Hepatocytes - drug effects; Humanities and Social Sciences; Humans; Hydroxycholesterols - pharmacology; Inflammation; Interleukin 6; Interleukin 6 receptors; Interleukin-6 - genetics; Liver; Liver - injuries; Liver - metabolism; Liver - pathology; Liver diseases; Liver Failure, Acute - drug therapy; Liver Failure, Acute - genetics; Liver Failure, Acute - pathology; Mice; multidisciplinary; Nuclear Receptor Subfamily 1, Group F, Member 1 - antagonists & inhibitors; Nuclear Receptor Subfamily 1, Group F, Member 1 - genetics; Primary Cell Culture; Retinoic acid; Science; Science (multidisciplinary); Signal transduction; Signal Transduction - drug effects; Stat3 protein; STAT3 Transcription Factor - genetics; Therapeutic applications; Transcription activation
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-48171-8

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.