Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates the toxic activity of many environmental xenobiotics. However, its role in innate immune responses during viral infection is not fully understood. Here we demonstrate that constitutive AHR signaling negatively regulates the type I interferon (IFN-I) response during infection with various types of virus. Virus-induced IFN-β production was enhanced in AHR- IFN-I-mediated innate response and, further, suggests that the AHR-TIPARP axis is a potential therapeutic target for enhancing antiviral responses.AHR was originally discovered as a xenobiotic sensor that mediates the toxicity of the persistent environmental contaminant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), more commonly known as dioxin [1][2][3][4] . Activation of AHR induces its target genes, including those encoding cytochrome P4501A1, cytochrome P4501B1, AHR repressor, TCDD-inducible poly(ADP-ribose)polymerase (TIPARP) and aldehyde dehydrogenase 1A3 (refs. 1,2,5-9), which are involved in the adaptive metabolism of xenobiotic compounds. This property of AHR has been implicated in host defense against bacterial infection, as certain bacterial pigmented virulence factors are AHR agonists that are subsequently metabolized by AHR-regulated drug-metabolizing enzymes 10 . Studies of AHR-deficient mice have identified important physiological roles for AHR in response to endogenous ligands in cell cycle regulation, cell differentiation and immune responses 8,[11][12][13][14] . In relation to this, several putative endogenous ligands for the AHR have also been reported, including heme metabolites, arachidonic acids or leukotrienes and tryptophan metabolites, such as 6-formylindolo(3,2-b)carbazole (FICZ) and kynurenine (Kyn) 2,8,15 .There has been increased interest in understanding the role of AHR in immunity.Several reports, most of which are based mainly on experiments with dioxin treatment, have shown that the AHR is involved in the differentiation and/or function of T cells, macrophages and dendritic cells 7,9,11,[16][17][18][19][20][21] . AHR has been implicated in the control of acute graft-versus-host disease and autoimmunity 11,12,21 . Dioxin-activated AHR also reduces the survival rate of mice infected with influenza A virus 22,23 and indirectly suppresses the proliferation and differentiation of virus-specific CD8 + T cells via its regulatory role in dendritic cells 24 . FICZ and dioxin diminish CD8 + T cell responsiveness, whereas dioxin, but not FICZ, affects neutrophil recruitment or pulmonary inducible nitric oxide synthase (iNOS) induction in response to influenza virus infection 25 .Tryptophan metabolites such as Kyn are upregulated during inflammation and/or tumor progression in several types of immune and tumor cells through the catalytic activity of tryptophan dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO), which catalyze the first step in the formation of Kyn from tryptophan 2,9 . This increase in Kyn leads to an increase in regulatory T c...

Background:Tiparp is an aryl hydrocarbon receptor (AHR) repressor, but its role in dioxin toxicity is unknown. Results: Loss of Tiparp increases sensitivity to dioxin toxicity and lethality. Tiparp ADP-ribosylates AHR, which is reversed by the mono-ADP-ribosylase, MacroD1. Conclusion: We identify new roles for Tiparp, MacroD1, and ADP-ribosylation in AHR signaling and dioxin toxicity. Significance: These data reveal the importance of TIPARP in regulating AHR activity in mice.

Members of the poly-ADP-ribose polymerase (PARP) family catalyse the ADP-ribosylation of target proteins and are known to play important roles in many cellular processes, including DNA repair, differentiation and transcription. The majority of PARPs exhibit mono-ADP-ribosyltransferase activity rather than PARP activity; however, little is known about their biological activity. In the present study, we report that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible poly-ADP-ribose polymerase (TIPARP), mono-ADP-ribosylates and positively regulates liver X receptor α (LXRα) and LXRβ activity. Overexpression of TIPARP enhanced LXR-reporter gene activity. TIPARP knockdown or deletion reduced LXR regulated target gene expression levels in HepG2 cells and in Tiparp(-/-)mouse embryonic fibroblasts (MEFs) respectively. Deletion and mutagenesis studies showed that TIPARP's zinc-finger and catalytic domains were required to enhance LXR activity. Protein interaction studies using TIPARP and LXRα/β peptide arrays revealed that LXRs interacted with an N-terminal sequence (a.a. 209-236) of TIPARP, which also overlapped with a putative co-activator domain of TIPARP (a.a. 200-225). Immunofluorescence studies showed that TIPARP and LXRα or LXRβ co-localized in the nucleus.In vitroribosylation assays provided evidence that TIPARP mono-ADP-ribosylated both LXRα and LXRβ. Co-immunoprecipitation (co-IP) studies revealed that ADP-ribosylase macrodomain 1 (MACROD1), but not MACROD2, interacted with LXRs in a TIPARP-dependent manner. This was complemented by reporter gene studies showing that MACROD1, but not MACROD2, prevented the TIPARP-dependent increase in LXR activity. GW3965-dependent increases in hepatic Srebp1 mRNA and protein expression levels were reduced in Tiparp(-/-)mice compared with Tiparp(+/+)mice. Taken together, these data identify a new mechanism of LXR regulation that involves TIPARP, ADP-ribosylation and MACROD1.

TCDD-inducible poly-ADP-ribose polymerase (TIPARP) is an aryl hydrocarbon receptor (AHR) target gene that functions as part of a negative feedback loop to repress AHR activity. Tiparp−/− mice exhibit increased sensitivity to the toxicological effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), including lethal wasting syndrome. However, it is not known whether Tiparp−/− mice also exhibit increased sensitivity to other AHR ligands. In this study, we treated male Tiparp−/− or wild type (WT) mice with a single injection of 100 mg/kg 3-methylcholanthrene (3MC). Consistent with TIPARP’s role as a repressor of AHR signaling, 3MC-treated Tiparp−/− mice exhibited increased hepatic Cyp1a1 and Cyp1b1 levels compared with WT mice. No 3MC-treated Tiparp−/− mice survived beyond day 16 and the mice exhibited chylous ascites characterized by an accumulation of fluid in the peritoneal cavity. All WT mice survived the 30-day treatment and showed no signs of fluid accumulation. Treated Tiparp−/− mice also exhibited a transient and mild hepatotoxicity with inflammation. 3MC-treated WT, but not Tiparp−/− mice, developed mild hepatic steatosis. Lipid deposits accumulated on the surface of the liver and other abdominal organs in the 3MC-Tiparp−/− mice. Our study reveals that Tiparp−/− mice have increased sensitivity to 3MC-induced liver toxicity, but unlike with TCDD, lethality is due to chylous ascites rather than wasting syndrome.

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