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Crifo, Bianca; Schaible, Bettina; Brown, Eric; Halligan, Doug N.; Scholz, Carsten C.; Fitzpatrick, Susan F.; Kirwan, Anna; Roche, Helen M.; Criscuoli, Mattia; Naldini, Antonella; Giffney, Hugh; Crean, Daniel; Blanco, Alfonso; Cavadas, Miguel A.; Cummins, Eoin P.; Fabian, Zsolt; Taylor, Cormac T.

Hydroxylase Inhibition Selectively Induces Cell Death in Monocytes

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  • Medientyp: E-Artikel
  • Titel: Hydroxylase Inhibition Selectively Induces Cell Death in Monocytes
  • Beteiligte: Crifo, Bianca; Schaible, Bettina; Brown, Eric; Halligan, Doug N.; Scholz, Carsten C.; Fitzpatrick, Susan F.; Kirwan, Anna; Roche, Helen M.; Criscuoli, Mattia; Naldini, Antonella; Giffney, Hugh; Crean, Daniel; Blanco, Alfonso; Cavadas, Miguel A.; Cummins, Eoin P.; Fabian, Zsolt; Taylor, Cormac T.
  • Erschienen: The American Association of Immunologists, 2019
  • Erschienen in: The Journal of Immunology
  • Sprache: Englisch
  • DOI: 10.4049/jimmunol.1800912
  • ISSN: 1550-6606; 0022-1767
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:title>Abstract</jats:title> <jats:p>Hypoxia is a common and prominent feature of the microenvironment at sites of bacteria-associated inflammation in inflammatory bowel disease. The prolyl-hydroxylases (PHD1/2/3) and the asparaginyl-hydroxylase factor-inhibiting HIF are oxygen-sensing enzymes that regulate adaptive responses to hypoxia through controlling the activity of HIF and NF-κB–dependent transcriptional pathways. Previous studies have demonstrated that the pan-hydroxylase inhibitor dimethyloxalylglycine (DMOG) is effective in the alleviation of inflammation in preclinical models of inflammatory bowel disease, at least in part, through suppression of IL-1β–induced NF-κB activity. TLR-dependent signaling in immune cells, such as monocytes, which is important in bacteria-driven inflammation, shares a signaling pathway with IL-1β. In studies into the effect of pharmacologic hydroxylase inhibition on TLR-induced inflammation in monocytes, we found that DMOG selectively triggers cell death in cultured THP-1 cells and primary human monocytes at concentrations well tolerated in other cell types. DMOG-induced apoptosis was independent of increased caspase-3/7 activity but was accompanied by reduced expression of the inhibitor of apoptosis protein 1 (cIAP1). Based on these data, we hypothesize that pharmacologic inhibition of the HIF-hydroxylases selectively targets monocytes for cell death and that this may contribute to the anti-inflammatory activity of HIF-hydroxylase inhibitors.</jats:p>
  • Zugangsstatus: Freier Zugang