title: Regulation of IDO activity by oxygen supply: inhibitory effects on antimicrobial and immunoregulatory functions.
abstract: Tryptophan is an essential amino acid for human beings as well as for some microorganisms. In human cells the interferon-γ (IFN-γ) inducible enzyme indoleamine 2,3-dioxygenase (IDO) reduces local tryptophan levels and is therefore able to mediate broad-spectrum effector functions: IDO activity restricts the growth of various clinically relevant pathogens such as bacteria, parasites and viruses. On the other hand, it has been observed that IDO has immunoregulatory functions as it efficiently controls the activation and survival of T-cells. Although these important effects have been analysed in much detail, they have been observed in vitro using cells cultured in the presence of 20% O₂ (normoxia). Such high oxygen concentrations are not present in vivo especially within infected and inflamed tissues. We therefore analysed IDO-mediated effects under lower oxygen concentrations in vitro and observed that the function of IDO is substantially impaired in tumour cells as well as in native cells. Hypoxia led to reduced IDO expression and as a result to reduced production of kynurenine, the downstream product of tryptophan degradation. Consequently, effector functions of IDO were abrogated under hypoxic conditions: in different human cell lines such as tumour cells (glioblastoma, HeLa) but also in native cells (human foreskin fibroblasts; HFF) IDO lost the capacity to inhibit the growth of bacteria (Staphylococcus aureus), parasites (Toxoplasma gondii) or viruses (herpes simplex virus type 1). Additionally, IDO could no longer efficiently control the proliferation of T-cells that have been co-cultured with IDO expressing HFF cells in vitro. In conclusion, the potent antimicrobial as well as immunoregulatory functions of IDO were substantially impaired under hypoxic conditions that pathophysiologically occurs in vivo.
authors.affiliation: Institute of Medical Microbiology and Hospital Hygiene, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
authors.forename: Silvia K
authors.initials: SK
authors.lastname: Schmidt
authors.forename: Sebastian
authors.initials: S
authors.lastname: Ebel
authors.forename: Eric
authors.initials: E
authors.lastname: Keil
authors.forename: Claudia
authors.initials: C
authors.lastname: Woite
authors.forename: Joachim F
authors.initials: JF
authors.lastname: Ernst
authors.forename: Anika E
authors.initials: AE
authors.lastname: Benzin
authors.forename: Jan
authors.initials: J
authors.lastname: Rupp
authors.forename: Walter
authors.initials: W
authors.lastname: Däubener
mesh_terms: D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018920:Coculture Techniques; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology* / Q000382:microbiology / Q000469:parasitology / Q000821:virology; D018259:Herpesvirus 1, Human / Q000254:growth & development; D054884:Host-Pathogen Interactions; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010100:Oxygen / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000254:growth & development; D013601:T-Lymphocytes / Q000166:cytology* / Q000502:physiology; D014122:Toxoplasma / Q000254:growth & development
chemical_list: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D010100:Oxygen