nor-Binaltorphimine dihydrochloride br Does TIPARP contribut

Does TIPARP contribute to the diverse species sensitivity to TCDD toxicity? In chick embryo hepatocytes TIPARP was reported to mediate the TCDD-dependent suppression of hepatic gluconeogenesis, by reducing cellular NAD+ levels and reducing PCK1 expression, suggesting that ADP-ribosylation enhances rather than represses AHR activity [26,55]. However, reduced PCK1 mRNA levels, serum glucose levels and liver NAD+ levels are also observed in TCDD-treated Tiparp deficient mice [48]. The reason for these disparities is unclear, but may reflect species, or in vitro versus in vivo differences. Unlike human or mouse TIPARP, chicken TIPARP did not repress human AHR activity in transfected human cell lines [27]. Moreover, it is possible that a PARP with poly-ADP-polymerase activity, such as PARP1, is responsible for the reduction in cellular NAD+ levels. Although additional studies in different species are needed, these reports support an important role for TIPARP, ADP-ribosylation and NAD+ in AHR signaling, but suggest that the nature of the outcome may be species-, cell- and context-specific. Humans are less sensitive to TCDD toxicities compared with laboratory rodents. Occupational cohorts with high dose TCDD exposure, develop chloracne, have a small increased cancer risk, but do not show signs of wasting syndrome and metabolic failure seen in laboratory rodents [56]. Guinea pigs are extremely sensitive to TCDD-induced lethality with a reported LD50 ranging from 1 to 2 μg/kg, while the LD50 for hamsters, one of the most resistant species, is 5000 μg/kg [1,57]. Although the role of TIPARP in AHR signaling in guinea pigs and hamsters has not been described, it is tempting to speculate that differences in the AHR-TIPARP axis and/or signaling pathways downstream of TIPARP contribute to the vast differences in sensitivity to TCDD toxicities among species. Developing non-murine Tiparp nor-Binaltorphimine dihydrochloride models using gene targeting would address whether loss of Tiparp would increase their sensitivity to TCDD in other commonly used laboratory test species. These models would also allow us to better predict TIPARP's role in protecting humans and other species against the toxic effects of TCDD.
TIPARP modulates endogenously regulated AHR activity in innate immunity Although TIPARP regulates AHR activity in response to TCDD, an important question is whether TIPARP also regulates endogenous ligand activated AHR. Of the numerous endogenous AHR ligands that have been identified, kynurenine (KYN), a metabolic breakdown product from tryptophan, has received a lot of interest as it is detected in vivo at concentrations that activate AHR [58]. Recently, TIPARP was shown to regulate the constitutive or KYN-dependent AHR-mediated repression of type I interferon (type-I-IFN) responses during viral infection [49]. KYN represses type-I-IFN responses during viral infection but increases this response in Ahr-deficient cells or mice. An increase in type-I-IFN responses is also seen with treatment with an AHR antagonist or an inhibitor targeting the KYN generating enzymes, indoleamine 2,3-dioxygenase/tryptophan 2,3-dioxygenase inhibitor. Repression of type-I-IFN after AHR activation is lost in Tiparp deficient cells. Mechanistically, TIPARP ADP-ribosylates the kinase domain of TANK binding kinase 1 (TBK1), reducing its ability to phosphorylate and activate interferon regulatory factor 3, causing reduced interferon β levels and consequently increased viral load [49]. These findings suggest that the AHR-TIPARP axis is a potential pharmacological target for antiviral therapy and reveal that TIPARP regulates both the toxic and biological activities of AHR. To what extent TIPARP and ADP-ribosylation contribute to other immune responses regulated by AHR will have to await future studies.
Concluding remarks The remarkable sensitivity of Tiparp deficient mice to TCDD-induced wasting syndrome and the contribution of TIPARP and ADP-ribosylation to AHR signaling, and lipid/energy homeostasis warrants further study to address a number of unanswered questions. How does TIPARP loss lead to increased sensitivity to TCDD toxicity? Is this due to over-activation of AHR, altered AHR function due to loss of ADP-ribosylation or an increase of another posttranslational modification on AHR? Is AHR signaling and TCDD toxicity regulated through on/off ADP-ribosylation by TIPARP and MACROD1 or other ADP-ribosyl hydrolases? It will be of significant interest to determine if MacroD1 deficient mice are protected from TCDD toxicity. The developmental defects and additional phenotypes reported in Tiparp deficient mice do, however, lessen their utility in studying TIPARP's role in AHR signaling and TCDD toxicity. Future studies using cell-specific Tiparp deletion and catalytic deficient Tiparp mutants will be needed to better define the role of TIPARP in AHR-signaling.