Hydroxylase Inhibition Selectively Induces Cell Death in Monocytes

J Immunol. 2019 Mar 1;202(5):1521-1530. doi: 10.4049/jimmunol.1800912. Epub 2019 Jan 30.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids, Dicarboxylic / pharmacology*
  • Cell Death / drug effects
  • Cell Death / immunology
  • Cells, Cultured
  • HEK293 Cells
  • Humans
  • Inflammation / drug therapy*
  • Inflammation / immunology
  • Inflammation / metabolism
  • Mixed Function Oxygenases / antagonists & inhibitors*
  • Mixed Function Oxygenases / immunology
  • Mixed Function Oxygenases / metabolism
  • Monocytes / drug effects*
  • Monocytes / immunology
  • Monocytes / metabolism
  • Prolyl-Hydroxylase Inhibitors / pharmacology*


  • Amino Acids, Dicarboxylic
  • Prolyl-Hydroxylase Inhibitors
  • Mixed Function Oxygenases
  • oxalylglycine