RORα suppresses interleukin-6-mediated hepatic acute phase response

초록

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 alpha (ROR alpha) limits APR-mediated liver injury by inhibiting the hepatic IL-6-STAT3 signaling pathway. Administration of JC1-40, an ROR alpha 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 ROR alpha activation by either adenoviral infusion of ROR alpha or JC1-40 treatment in primary hepatocytes. Activation of ROR alpha decreased transcriptional expression of IL-6 receptor alpha, an upstream activator of STAT3, both in vitro and in vivo. This may be one mechanism underlying the ROR alpha-mediated inhibition of STAT3. Taken together, our results suggest that ROR alpha 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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