Expression of indoleamine 2,3-dioxygenase, tryptophan degradation, and kynurenine formation during in vivo infection with Toxoplasma gondii: induction by endogenous gamma interferon and requirement of interferon regulatory factor 1.
The induction of indoleamine 2,3-dioxygenase (INDO) expression and the tryptophan (Trp)-kynurenine (Kyn) metabolic pathway during in vivo infection with Toxoplasma gondii was investigated. Decreased levels of Trp and increased formation of Kyn were observed in the lungs, brain, and serum from mice infected with T. gondii. Maximal INDO mRNA expression and enzyme activity were detected in the lungs at 10 to 20 days postinfection. Further, the induction of INDO mRNA expression, Trp degradation and Kyn formation were completely absent in tissues from mice deficient in IFN-gamma (IFN-gamma(-/-)) or IFN regulatory factor -1 (IRF-1(-/-)). These findings indicate the important role of endogenous IFN-gamma and IRF-1 in the in vivo induction of the Trp-Kyn metabolic pathway during acute infection with T. gondii. In contrast, expression of INDO mRNA and its activity was preserved in the tissues of TNF-receptor p55- or inducible nitric oxide synthase-deficient mice infected with T. gondii. Together with the results showing the extreme susceptibility of the IFN-gamma(-/-) and the IRF-1(-/-) mice to infection with T. gondii, our results indicate a possible involvement of INDO and Trp degradation in host resistance to early infection with this parasite.
Silva
Neide M
NM
Department of Biochemistry and Immunology, UFMG, 31270-910 Belo Horizonte. Centro de Pesquisas René Rachou, FIOCRUZ, 30190-002 Belo Horizonte, Brazil.
Rodrigues
Cibele V
CV
Santoro
Marcelo M
MM
Reis
Luiz F L
LF
Alvarez-Leite
Jacqueline I
JI
Gazzinelli
Ricardo T
RT
D000208:Acute Disease; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D004198:Disease Susceptibility; D015870:Gene Expression; D050856:Interferon Regulatory Factor-1; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D007700:Kinetics; D007737:Kynurenine / Q000096:biosynthesis* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D012333:RNA, Messenger; D014122:Toxoplasma / Q000276:immunology; D014123:Toxoplasmosis / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D014364:Tryptophan / Q000276:immunology / Q000378:metabolism*; D014366:Tryptophan Oxygenase / Q000235:genetics* / Q000276:immunology / Q000378:metabolism
D004268:DNA-Binding Proteins; D050856:Interferon Regulatory Factor-1; C494258:Irf1 protein, mouse; D010750:Phosphoproteins; D012333:RNA, Messenger; D007737:Kynurenine; D007371:Interferon-gamma; D014364:Tryptophan; D014366:Tryptophan Oxygenase