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PMID: 10225879 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Replication of Toxoplasma gondii, but not Trypanosoma cruzi, is regulated in human fibroblasts activated with gamma interferon: requirement of a functional JAK/STAT pathway.

Infection and immunity ·Vol. 67 ·No. 5 ·1999-05-00 ·Pages 2233-40

Cerávolo IP, Chaves AC, Bonjardim CA, Sibley D, Romanha AJ, Gazzinelli RT

Abstract

To study the role of tryptophan degradation by indoleamine 2, 3-dioxygenase (INDO) in the control of Trypanosoma cruzi or Toxoplasma gondii replication, we used human fibroblasts and a fibrosarcoma cell line (2C4). The cells were cultured in the presence or absence of recombinant gamma interferon (rIFN-gamma) and/or recombinant tumor necrosis factor alpha (rTNF-alpha) for 24 h and were then infected with either T. cruzi or T. gondii. Intracellular parasite replication was evaluated 24 or 48 h after infection. Treatment with rIFN-gamma and/or rTNF-alpha had no inhibitory effect on T. cruzi replication. In contrast, 54, 73, or 30% inhibition of T. gondii replication was observed in the cells treated with rIFN-gamma alone, rIFN-gamma plus rTNF-alpha, or TNF-alpha alone, respectively. The replication of T. gondii tachyzoites in cytokine-activated cells was restored by the addition of extra tryptophan to the culture medium. Similarly, T. gondii tachyzoites transfected with bacterial tryptophan synthase were not sensitive to the microbiostatic effect of rIFN-gamma. We also investigated the basis of the cytokine effect on parasite replication by using the three mutant cell lines B3, B9, and B10 derived from 2C4 and expressing defective STAT1alpha (signal transducer and activator of transcription), JAK2 (Janus family of cytoplasmic tyrosine kinases), or JAK1, respectively, three important elements of a signaling pathway triggered by rIFN-gamma. We found that rTNF-alpha was able to induce low levels expression of INDO mRNA in the parental cell line, as well as the cell line lacking functional JAK2. In contrast to the parental cell line (2C4), rIFN-gamma was not able to induce the expression of INDO mRNA or microbiostatic activity in any of the mutant cell lines. These findings indicate the essential requirement of the JAK/STAT pathway for the induction of high levels of INDO mRNA, tryptophan degradation, and the anti-Toxoplasma activity inside human nonprofessional phagocytic cells.

MeSH Terms
Animals Base Sequence Cell Division/drug effects Cell Line DNA Primers/genetics DNA-Binding Proteins/genetics,metabolism Fibroblasts Gene Expression/drug effects Humans Interferon-gamma/pharmacology Janus Kinase 1 Janus Kinase 2 Mutation Protein-Tyrosine Kinases/genetics,metabolism Proto-Oncogene Proteins RNA, Messenger/genetics,metabolism Recombinant Proteins/pharmacology STAT1 Transcription Factor Toxoplasma/growth & development,metabolism,pathogenicity Trans-Activators/genetics,metabolism Transfection Trypanosoma cruzi/growth & development,metabolism,pathogenicity Tryptophan/metabolism Tryptophan Oxygenase/genetics,metabolism Tumor Necrosis Factor-alpha/pharmacology
Chemicals
DNA Primers DNA-Binding Proteins Proto-Oncogene Proteins RNA, Messenger Recombinant Proteins STAT1 Transcription Factor STAT1 protein, human Trans-Activators Tumor Necrosis Factor-alpha Interferon-gamma Tryptophan Tryptophan Oxygenase Protein-Tyrosine Kinases JAK1 protein, human JAK2 protein, human Janus Kinase 1 Janus Kinase 2
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Cerávolo I P
Cellular and Molecular Parasitology Laboratory, Centro de Pesquisas René Rachou, FIOCRUZ, ICB, UFMG, Belo Horizonte, Brazil.
Chaves A C
Bonjardim C A
Sibley D
Romanha A J
Gazzinelli R T
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Article Info
Journal
Infection and immunity
Abbr.
Infect Immun
ISSN
0019-9567
DOI
10.1128/IAI.67.5.2233-2240.1999
Published
1999-05-00
Pages
2233-40
Language
English
Region
United States
NLM ID
0246127
PMCID
PMC115962
Subset
IM
External Links
PubMed source DOI: 10.1128/IAI.67.5.2233-2240.1999 PMC Full Text View journal details
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