Cytokine-mediated indoleamine 2,3-dioxygenase induction in response to Chlamydia infection in human macrophage cultures.
The purpose of this study was to characterize further the events leading to the metabolic degradation of tryptophan in Chlamydia-infected cultures in the absence of added interferon (IFN). Macrophages on coverslips were infected with Chlamydia psittaci, and tryptophan decyclization was determined 24 h later by reverse-phase high-performance liquid chromatography. Tryptophan metabolites cochromatographed with kynurenine and N-formylkynurenine, the end products of tryptophan decyclization by the IFN-inducible enzyme indoleamine 2,3-dioxygenase (IDO). Although chloramphenicol pretreatment completely inhibited chlamydial replication, IDO was stimulated to an extent similar to that in untreated, infected cells. No IDO induction was observed in cells pretreated with cycloheximide even though chlamydial growth was slightly greater than in untreated cells. These results indicate that enhanced tryptophan decyclization was due to induction of IDO. IDO induction was dependent on the size of the chlamydial inoculum. Heat- or UV-inactivated chlamydiae induced significantly less IDO activity than viable chlamydiae. Culture supernatants from Chlamydia-infected macrophages induced IDO activity in a dose-dependent manner, suggesting that a secreted product of infected cells was responsible for IDO induction. A combination of neutralizing antibodies to IFN-alpha and IFN-beta inhibited induction of IDO activity by infected cell culture supernatants. Furthermore, IL-1 enzyme-linked immunosorbent assay results indicated the accumulation of IL-1 beta in the culture medium. Thus, induction of IDO in Chlamydia-infected macrophages reflects the production of cytokines in response to infection and may represent a normal host cell response to control intracellular infection.
Paguirigan
A M
AM
Department of Microbiology, Miami University, Oxford, Ohio 45056.
Byrne
G I
GI
Becht
S
S
Carlin
J M
JM
D000328:Adult; D002478:Cells, Cultured; D002691:Chlamydophila psittaci / Q000472:pathogenicity*; D016207:Cytokines / Q000502:physiology*; D004790:Enzyme Induction; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007375:Interleukin-1 / Q000096:biosynthesis; D008264:Macrophages / Q000378:metabolism* / Q000382:microbiology; D014364:Tryptophan / Q000378:metabolism; D014366:Tryptophan Oxygenase / Q000096:biosynthesis*
D016207:Cytokines; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007375:Interleukin-1; D014364:Tryptophan; D014366:Tryptophan Oxygenase