Unknown,Transcriptomics,Genomics,Proteomics

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Transcription profiling of murine dendritic cells in the presence and absence of interferon (IFN)-gamma to identify a tolerogenic signature in IDO-competent dendritic cells.

ABSTRACT: Although much is known on the transcriptional profiles of dendritic cells (DCs) during maturation, the molecular switches critical for the acquisition of a tolerogenic program by DCs are still obscure. In the present study, we explored the gene expression pattern of CD8+ DCs purified from the mouse spleen and treated with interferon (IFN)-gamma. The cytokine, indeed, potentiates the tolerogenic potential of this DC subset via induction of the immunosuppressive tryptophan catabolism mediated by indoleamine 2,3-dioxygenase (IDO). By comparing the expression of the IFN-gamma-modulated genes in IDO+ versus IDO- murine DCs, we found a consistent and selective association of the IDO-competent phenotype with the down-modulation of the Tyrobp gene, encoding the adapter molecule DAP12. IFN-gamma-mediated down-modulation of this gene involved IFN consensus sequence binding protein (ICSBP), a transcription factor also known as IRF-8. While silencing of Tyrobp conferred IDO functional competence on IDO- DCs, silencing of Icsbp1 in IDO+ cells completely abolished IDO expression and function. In parallel, silencing of TYROBP conferred IDO competence on human IDO- DCs while silencing of IRF8 impaired IDO expression and activity in human IDO+ DCs. Therefore, the same small set of molecular switches controls IDO competence in murine and human DCs. Experiment Overall Design: Labeled cRNA extracted from a a total of 8 samples was hybridized to the Affymetrix GeneChip MG-U74Av2 which contains 12,488 probe sets . The 4 control samples included 2 replicates each of RNA extracted from cells incubated in medium for 4 and 16 hours. Treated samples included 2 replicates each of RNA extracted from cells incubated in IFN-gammas for 4 and 16 hours.

ORGANISM(S): Mus musculus

SUBMITTER: Silvio Bicciato

PROVIDER: E-GEOD-3337 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Toward the identification of a tolerogenic signature in IDO-competent dendritic cells.

Orabona Ciriana C Puccetti Paolo P Vacca Carmine C Bicciato Silvio S Luchini Alessandra A Fallarino Francesca F Bianchi Roberta R Velardi Enrico E Perruccio Katia K Velardi Andrea A Bronte Vincenzo V Fioretti Maria Cristina MC Grohmann Ursula U

Blood 20051208 7

Although much is known about the transcriptional profiles of dendritic cells (DCs) during maturation, the molecular switches critical for the induction of a tolerogenic program in DC subsets are still obscure. We examined the gene-expression profiles of murine splenic CD8+ DCs rendered highly tolerogenic by interferon-gamma (IFN-gamma), which activates the enzyme indoleamine 2,3-dioxygenase (IDO, encoded by Indo) and thus initiates the immunosuppressive pathway of tryptophan catabolism. By exami ...[more]

PMID: 16339401

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Project description:Infection with Chlamydia pneumoniae, a human respiratory pathogen, has been associated with various chronic diseases such as asthma, coronary heart disease and importantly atherosclerosis. Possibly because the pathogen can exist in a persistent form. TNF-a has been reported to induce chlamydial persitence in epithelial cell lines, however the mechanism of TNF-a-induced persistence has not been reported. Moreover, C. pneumoniae persistently infect human dendritic cells (DCs) and activate DCs to produce cytokines including TNF-a. Induction of chlamydial persistence by other cytokines such as IFN-g is known to be due to indoleamine 2,3-dioxygenase (IDO) activity. The present study therefore, investigated whether C. pneumoniae infection can induce IDO activity in dendritic cells, and whether the restriction of chlamydial growth in the DCs by TNF-a is IDO-dependent. Our data indicate that infection of DCs with C. pneumoniae resulted in the induction of IDO expression. Reporting on our use of anti-TNF-a antibody adalimumab and varying concentrations of TNF-a, we further demonstrate that IDO induction following infection of DCs with C. pneumoniae is TNF-a-dependent. The anti-chlamydial activity induced by TNF-a and the expression of chlamydial 16S rRNA gene, euo, groEL1, ftsk and tal genes was correlated with the induction of IDO. Addition of excess amounts of tryptophan to the DC cultures resulted in abrogation of the TNF-a-mediated chlamydial growth restriction. These findings suggest that infection of DCs by C. pneumoniae induces production of functional IDO, which subsequently causes depletion of tryptophan. This may represent a potential mechanism for DCs to restrict bacterial growth in chlamydial infections. Experiment Overall Design: Human monocyte-derived DCs from five heathy donors were infected with C. pneumoniae at multiplicity of infection of 5 for 72 h. Mock-infected (uninfected) DCs were used as a control for the infection. Total RNA from 72 h chlamydiae-infected or mock-infected DCs was isolated with RNeasy Mini Kit (Qiagen, Hilden, Germany) and DNA contamination was removed with RQ1 DNase (Promega). Total RNA from all donors was pooled and the samples were processed and analyzed at the array facility of Helmholtz center for infection biology, Braunschweig. The integrity of the RNA was verified on the Agilent Bioanalyzer system. We used the Affymetrix Gene Chip Human Genome U133 2.0 Plus. Data were processed using Affymetrix software and signal intensity measured was normalized by the Affymetrix MAS5 algorithm. Data were filtered to exclude genes at background levels (non-expressors, signal intensity at 100).

Dataset Information

Transcription profiling of murine dendritic cells in the presence and absence of interferon (IFN)-gamma to identify a tolerogenic signature in IDO-competent dendritic cells.

Publications

Toward the identification of a tolerogenic signature in IDO-competent dendritic cells.

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