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Expression of Indoleamine 2,3-Dioxygenase Induced by IFN-γ and TNF-α as Potential Biomarker of Prostate Cancer Progression.

ABSTRACT: Inflammation has been suggested to play an important role in onset and progression of prostate cancer (PCa). Histological analysis of prostatectomy specimens has revealed focal inflammation in early stage lesions of this malignancy. We addressed the role of inflammatory stimuli in the release of PCa-specific, tumor-derived soluble factors (PCa-TDSFs) already reported to be mediators of PCa morbidity, such as indoleamine 2,3-dioxygenase (IDO) and interleukin (IL)-6. Inflammation-driven production and functions of PCa-TDFSs were tested "in vitro" by stimulating established cell lines (CA-HPV-10 and PC3) with IFN-γ or TNF-α. Expression of genes encoding IDO, IL-6, IFN-γ, TNF-α, and their receptors was investigated in tumor tissues of PCa patients undergoing radical prostatectomy, in comparison with benign prostatic hyperplasia (BPH) specimens. IFN-γ and TNF-α-treatment resulted in the induction of IDO and IL-6 gene expression and release in established cell lines, suggesting that the elicitation of PCa-TDSFs by these cytokines might contribute to progression of cancer into an untreatable phenotype. An analysis based on timing of biochemical recurrence revealed the prognostic value of IDO but not IL-6 gene expression in predicting recurrence-free survival in patients (RFS) with PCa. In addition, a urine-based mRNA biomarker study revealed the diagnostic potential of IDO gene expression in urines of men at risk of PCa development.

SUBMITTER: Banzola I

PROVIDER: S-EPMC5986916 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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).

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Expression of Indoleamine 2,3-Dioxygenase Induced by IFN-γ and TNF-α as Potential Biomarker of Prostate Cancer Progression.

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