title: Negative Impact of Hypoxia on Tryptophan 2,3-Dioxygenase Function.
abstract: Tryptophan is an essential amino acid for hosts and pathogens. The liver enzyme tryptophan 2,3-dioxygenase (TDO) provokes, by its ability to degrade tryptophan to N-formylkynurenine, the precursor of the immune-relevant kynurenines, direct and indirect antimicrobial and immunoregulatory states. Up to now these TDO-mediated broad-spectrum effector functions have never been observed under hypoxia in vitro, although physiologic oxygen concentrations in liver tissue are low, especially in case of infection. Here we analysed recombinant expressed human TDO and ex vivo murine TDO functions under different oxygen conditions and show that TDO-induced restrictions of clinically relevant pathogens (bacteria, parasites) and of T cell proliferation are abrogated under hypoxic conditions. We pinpointed the loss of TDO efficiency to the reduction of TDO activity, since cell survival and TDO protein levels were unaffected. In conclusion, the potent antimicrobial as well as immunoregulatory effects of TDO were substantially impaired under hypoxic conditions that pathophysiologically occur in vivo. This might be detrimental for the appropriate host immune response towards relevant pathogens.
authors: Institute of Medical Microbiology and Hospital Hygiene, Heinrich-Heine-University, 40225 Düsseldorf, Germany.
authors: Frank
authors: F
authors: Elbers
authors: Institute of Medical Microbiology and Hospital Hygiene, Heinrich-Heine-University, 40225 Düsseldorf, Germany.
authors: Claudia
authors: C
authors: Woite
authors: Institute of Medical Microbiology and Hospital Hygiene, Heinrich-Heine-University, 40225 Düsseldorf, Germany.
authors: Valentina
authors: V
authors: Antoni
authors: Institute of Medical Microbiology and Hospital Hygiene, Heinrich-Heine-University, 40225 Düsseldorf, Germany.
authors: Sara
authors: S
authors: Stein
authors: Center for Advanced Research and Education, Asahikawa Medical University, Asahikawa 078-8510, Japan.
authors: Hiroshi
authors: H
authors: Funakoshi
authors: Neurogen Inc., 1-1-52-201 Nakahozumi, Ibaraki 567-0034, Japan.
authors: Toshikazu
authors: T
authors: Nakamura
authors: Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Institute of Epidemiology, 17493 Greifswald-Insel Riems, Germany.
authors: Gereon
authors: G
authors: Schares
authors: Institute of Medical Microbiology and Hospital Hygiene, Heinrich-Heine-University, 40225 Düsseldorf, Germany.
authors: Walter
authors: W
authors: Däubener
authors: Institute of Medical Microbiology and Hospital Hygiene, Heinrich-Heine-University, 40225 Düsseldorf, Germany.
authors: Silvia K
authors: 0000-0002-4106-3695
authors: SK
authors: Eller
mesh_terms: D000818:Animals; D015687:Cell Hypoxia / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D049109:Cell Proliferation / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D013293:Enterococcus faecalis / Q000276:immunology / Q000472:pathogenicity; D005347:Fibroblasts / Q000276:immunology / Q000382:microbiology / Q000469:parasitology; D006367:HeLa Cells; D006801:Humans; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018688:Neospora / Q000276:immunology / Q000472:pathogenicity; D013601:T-Lymphocytes / Q000166:cytology / Q000502:physiology; D014122:Toxoplasma / Q000276:immunology / Q000472:pathogenicity; D014366:Tryptophan Oxygenase / Q000235:genetics / Q000378:metabolism*
chemical_list: D014366:Tryptophan Oxygenase