TY - JOUR T1 - Aryl Hydrocarbon Receptor Dependent Stanniocalcin 2 Induction by Cinnabarinic Acid Provides Cytoprotection Against ER and Oxidative Stress JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.114.222265 SP - jpet.114.222265 AU - Aditya D. Joshi AU - Dwayne E. Carter AU - Tod A. Harper AU - Cornelis J. Elferink Y1 - 2015/01/01 UR - http://jpet.aspetjournals.org/content/early/2015/02/11/jpet.114.222265.abstract N2 - The Aryl Hydrocarbon Receptor (AhR) is a cytosolic ligand activated transcription factor historically known for its role in xenobiotic metabolism. Although AhR activity has previously been shown to play a cytoprotective role against intrinsic apoptotic stimuli, the underlying mechanism by which AhR confers cytoprotection against apoptosis is largely unknown. Here, we demonstrate that activation of AhR by the tryptophan catabolite, cinnabarinic acid (CA) directly upregulates expression of Stanniocalcin 2 (Stc2) to elicit cytoprotection against ER stress and oxidative stress induced apoptosis. Chromatin immunoprecipitation studies demonstrated that CA treatment induces direct AhR binding to a region of the Stc2 promoter containing multiple Xenobiotic Response Elements (XRE). Using isolated primary hepatocytes from AhR wild-type (AhR floxed) and liver specific AhR conditional knockout (AhR CKO) mice, we showed that pretreatment with CA conferred cytoprotection against hydrogen peroxide (H2O2), thapsigargin and ethanol induced apoptosis in an AhR dependent manner. Furthermore, suppressing Stc2 expression using RNA interference confirmed that the cytoprotective properties of CA against H2O2, thapsigargin and ethanol injury were absolutely dependent on Stc2. Immunochemistry revealed the presence of Stc2 in the endoplasmic reticulum and on the cell surface, consistent with Stc2 secretion and autocrine and/or paracrine signaling. Finally in vivo data using a mouse model of acute alcohol hepatotoxicity demonstrated that CA provided cytoprotection against ethanol induced apoptosis, hepatic microvesicular steatosis and liver injury. Collectively our data uncovered a novel mechanism for AhR-mediated cytoprotection in the liver that is dependent on CA induced Stc2 activity. ER -