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Hypoxia abrogates antichlamydial properties of IFN-? in human fallopian tube cells in vitro and ex vivo.

ABSTRACT: IFN-? has an important role in the adaptive immune response against intracellular pathogens. In urogenital tract (UGT) infections with the obligate intracellular pathogen Chlamydia trachomatis, IFN-?-mediated control of chlamydial growth implies the JAK-STAT signaling cascades and subsequent induction of the indoleamine 2,3-dioxygenase (IDO). As oxygen concentrations in the UGT are low under physiological conditions (O(2) < 5%) and further decrease during an inflammatory process, we wondered whether antibacterial properties of IFN-? are maintained under hypoxic conditions. Using primary cells that were isolated from human fallopian tubes and an ex vivo human fallopian tube model (HFTM), we found that even high IFN-? concentrations (200 units/mL) were not sufficient to limit growth of C. trachomatis under hypoxia. Reduced antibacterial activity of IFN-? under hypoxia was restricted to the urogenital serovars D and L(2), but was not observed with the ocular serovar A. Impaired effectiveness of IFN-? on chlamydial growth under hypoxia was accompanied by reduced phosphorylation of Stat-1 on Tyr701 and diminished IDO activity. This study shows that IFN-? effector functions on intracellular C. trachomatis depend on the environmental oxygen supply, which could explain inadequate bacterial clearance and subsequent chronic infections eventually occurring in the UGT of women.

SUBMITTER: Roth A

PROVIDER: S-EPMC2984208 | biostudies-other | 2010 Nov

REPOSITORIES: biostudies-other

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Hypoxia abrogates antichlamydial properties of IFN-γ in human fallopian tube cells in vitro and ex vivo.

Roth Anna A König Peter P van Zandbergen Ger G Klinger Matthias M Hellwig-Bürgel Thomas T Däubener Walter W Bohlmann Michael K MK Rupp Jan J

Proceedings of the National Academy of Sciences of the United States of America 20101025 45

IFN-γ has an important role in the adaptive immune response against intracellular pathogens. In urogenital tract (UGT) infections with the obligate intracellular pathogen Chlamydia trachomatis, IFN-γ-mediated control of chlamydial growth implies the JAK-STAT signaling cascades and subsequent induction of the indoleamine 2,3-dioxygenase (IDO). As oxygen concentrations in the UGT are low under physiological conditions (O(2) < 5%) and further decrease during an inflammatory process, we wondered whe ...[more]

PMID: 20974954

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Project description:High-grade serous cancer (HGSC) progresses to advanced stages without symptoms and the 5-year survival rate is a dismal 30%. Recent studies of ovaries and Fallopian tubes in patients with BRCA1 or BRCA2 mutations have documented a pre-metastatic intramucosal neoplasm that is found almost exclusively in the Fallopian tube, termed 'serous tubal intraepithelial carcinoma' or STIC. Moreover, other proliferations, termed p53 signatures, secretory cell outgrowths (SCOUTs), and lower-grade serous tubal intraepithelial neoplasms (STINs) fall short of STIC but share similar alterations in expression, in keeping with an underpinning of genomic disturbances involved in, or occurring in parallel with, serous carcinogenesis. To gain insight into the cellular origins of this unique tubal pathway to high-grade serous cancer, we cloned and both immortalized and transformed Fallopian tube stem cells (FTSCs). We demonstrated that pedigrees of FTSCs were capable of multipotent differentiation and that the tumours derived from transformed FTSCs shared the histological and molecular features of HGSC. We also demonstrated that altered expression of some biomarkers seen in transformed FTSCs and HGSCs (stathmin, EZH2, CXCR4, CXCL12, and FOXM1) could be seen as well in immortalized cells and their in vivo counterparts SCOUTs and STINs. Thus, a whole-genome transcriptome analysis comparing FTSCs, immortalized FTSCs, and transformed FTSCs showed a clear molecular progression sequence that is recapitulated by the spectrum of accumulated perturbations characterizing the range of proliferations seen in vivo. Biomarkers unique to STIC relative to normal tubal epithelium provide a basis for novel detection approaches to early HGSC, but must be viewed critically given their potential expression in lesser proliferations. Perturbations shared by both immortalized and transformed FTSCs may provide unique early targets for prevention strategies. Central to these efforts has been the ability to clone and perpetuate multipotent FTSCs.

Project description:ObjectivesRecent research shows that most high grade ovarian cancer (OC) originates from the fallopian tube (FT). Cytologic evaluation of FT cells may enable early detection of OC.Material and methodsThis was a prospective study with patients enrolled from 3 centers (October 2016- August 2017). Forty-two women undergoing salpingo-oophorectomy for a pelvic mass suspicious for malignancy or undergoing risk-reducing surgery for BRCA mutations were included in the study. At the time of scheduled surgery, a novel catheter was used to collect FT cells through hysteroscopy. A pathologist blinded to surgical or pathologic findings evaluated FT cytology, and results were compared to pathology.ResultsOf the 61 samples collected, 72% (44/61) met the adequacy criteria (≥5 clusters of cells with 20 cells in each cluster). Cytology classification criteria were established and applied to adequate samples. Forty-four samples were benign with mixed population of cells with round, oval, and spindled nuclei; 2-dimensional clusters; columnar cell configuration; flat sheets; cilia presence; no/mild nuclear pleomorphism; no nuclear membrane irregularities; and no nucleoli. Five samples had benign features with reactive nuclear and cytoplasmic changes and/or background inflammation, which were categorized as "reactive atypia." Two malignant samples had features of 3-dimensional (3D) clusters, loss of mixed population of cells; increased nuclear/cytoplasmic ratio; nuclear membrane irregularity and nucleoli presence. Three samples with some but not all of malignant features were categorized as "neoplastic" (anisonucleosis; small nucleoli and features suggestive of 3D clusters). Malignant/ neoplastic samples were labeled as "Positive" (n = 5) while benign/reactive samples were labeled as "Negative" (n = 39). A high concordance rate (95%, 42/44) was observed between cytology results and histology.ConclusionsWe characterized cytologic features for pathologically distinct FT samples collected in vivo using a novel catheter and demonstrated its value in detecting OC.

Dataset Information

Hypoxia abrogates antichlamydial properties of IFN-? in human fallopian tube cells in vitro and ex vivo.

Publications

Hypoxia abrogates antichlamydial properties of IFN-γ in human fallopian tube cells in vitro and ex vivo.

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