Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA232711 | ENA |
REPOSITORIES: ENA
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Project description:IFNb has been used as a first line therapy for relapsing remitting multiple sclerosis (RRMS). Since only a few studies have addressed the role of endogenous IFNb in the pathogenesis of the disease, our objective was to characterize its role in the transcriptional regulation of pathogenic Th17 cytokines in patients with RRMS. In-vitro studies have demonstrated that IFNb inhibited IL-17A, IL-17F, IL-21, IL-22 and IFN-b secretion in CD4+ lymphocytes through the induction of suppressor of cytokine secretion (SOCS)1 and 3. We found that patients with RRMS have increased serum and cerebrospinal fluid (CSF) Th17 (IL-17A and IL-17F) cytokine levels in comparison to the control subjects, suggesting that deficient endogenous IFNbeta secretion and/or signaling may contribute to the dysregulation of those pathogenic cytokines in CD4+ cells. We identified that the endogenous IFNb from serum of RRMS patients induced a significantly lower IFN-inducible gene expression in comparison to healthy controls (HCs). In addition, in-vitro studies have revealed a deficient endogenous and exogenous IFNb signaling in CD4+ cells derived from MS patients. Interestingly, upon inhibition of the endogenous IFNb signaling by silencing interferon regulatory factor (IRF)7 gene expression, the resting CD4+ T cells secreted significantly higher level of IL-17A, IL-17F, IL-21, IL-22 and IL-9, suggesting that endogenous IFNb suppresses the secretion of these pathogenic cytokines. In-vivo recombinant IFNb-1a treatment induced IFNAR1 and its downstream signaling moleculesM-bM-^@M-^Y gene expression, suggesting that treatment may reconstitute a deficient endogenous IFNbeta regulation of the CD4+ T-cellsM-bM-^@M-^Y pathogenic cytokine production in MS patients. Gene expression changes induced by IFNM-NM-2M-bM-^HM-^R1a were tested using Affymetrix Human Genome U133 (HG-U133) arrays (Affymetrix) that contain 45,000 probe sets representing 39,000 transcripts derived from approximately 33,000 human genes. 107 PBMCs per condition derived from 15 CIS patients were stimulated with plate-immobilized M-NM-1CD3 (1 M-NM-<g/ml) and M-NM-1CD28 (5 M-NM-<g/ml) mAb (BD Biosciences) in the absence or presence of IFNM-NM-2-1a (1000 U/ml) (EMD Serono Inc) for 24 h in serum-free medium (Gibco). Cells were harvested and the total RNA was isolated using a Rneasy kit (Quiagen). Arrays were hybridized for 16 hours at 45oC in the GeneChipM-BM-. Hybridization Oven 640 (Affymetrix). The arrays were washed and stained with R-phycoerythrin streptavidin in the GeneChipM-BM-. Fluidics Station 400 (Affymetrix). The arrays were scanned with a Hewlett Packard GeneArray Scanner. Affymetrix GeneChipM-BM-. Microarray Suite 5.0 software was used for washing, scanning and basic analysis.
2014-05-15 | E-GEOD-53716 | biostudies-arrayexpress
Project description:IFNb has been used as a first line therapy for relapsing remitting multiple sclerosis (RRMS). Since only a few studies have addressed the role of endogenous IFNb in the pathogenesis of the disease, our objective was to characterize its role in the transcriptional regulation of pathogenic Th17 cytokines in patients with RRMS. In-vitro studies have demonstrated that IFNb inhibited IL-17A, IL-17F, IL-21, IL-22 and IFN-b secretion in CD4+ lymphocytes through the induction of suppressor of cytokine secretion (SOCS)1 and 3. We found that patients with RRMS have increased serum and cerebrospinal fluid (CSF) Th17 (IL-17A and IL-17F) cytokine levels in comparison to the control subjects, suggesting that deficient endogenous IFNbeta secretion and/or signaling may contribute to the dysregulation of those pathogenic cytokines in CD4+ cells. We identified that the endogenous IFNb from serum of RRMS patients induced a significantly lower IFN-inducible gene expression in comparison to healthy controls (HCs). In addition, in-vitro studies have revealed a deficient endogenous and exogenous IFNb signaling in CD4+ cells derived from MS patients. Interestingly, upon inhibition of the endogenous IFNb signaling by silencing interferon regulatory factor (IRF)7 gene expression, the resting CD4+ T cells secreted significantly higher level of IL-17A, IL-17F, IL-21, IL-22 and IL-9, suggesting that endogenous IFNb suppresses the secretion of these pathogenic cytokines. In-vivo recombinant IFNb-1a treatment induced IFNAR1 and its downstream signaling molecules’ gene expression, suggesting that treatment may reconstitute a deficient endogenous IFNbeta regulation of the CD4+ T-cells’ pathogenic cytokine production in MS patients.
2014-05-15 | GSE53716 | GEO
Project description:Rationale: Humans encode 12 different IFNa proteins. All of them, except IFNa1 (only binds with IFNAR1), bind with IFNAR1 and IFNAR2 to activate their downstream functions. Currently in the field, it is still a debate whether there are qualitative difference between different IFNa subtypes or the differences are merely quantitative. The current study was set out to elucidate the question. Methods: Commercially purchased PBMCs from 7 donors were mock treated or with ISRE activity normalized IFNa1, IFNa2, IFNa4, IFNa5, IFNa8, IFNa14, or IFNb. RNAs were extracted from cells after 18 hrs of incubation. RNASeq libraries were generated using Lexogen Quant Seq 3’ mRNA-Seq library (FWD) Prep Kit. RNASeq were performed on Illumina NovaSEQ6000. Results: An average of 12.6 million gene counts were identified for each donor/treatment. A total of 50,133 genes were mapped, and among them 333 genes were differentially expressed due to type I interferon treatments. Each of IFNa subtypes or IFNb has their specifically regulated genes in PBMCs. Conclusion: These are the further evidences that there are qualitative differences between type I interferons.
2023-12-01 | GSE191317 | GEO
Project description:Our results introduce interleukin (IL)-11 as a new cytokine that may play a role in the development of the autoimmune response in patients with relapsing remitting multiple sclerosis (RR MS). IL-11 was found to be the highest up-regulated cytokine in the serum and cerebrospinal fluid (CSF) from patients with clinically isolated syndrome (CIS) suggestive of MS. It was also increased in the serum and CSF of patients with clinically definitive RRMS and during the clinical relapses of the disease. CD4+ cells represent a predominant cell source of IL-11 in the peripheral circulation, and the percentage of IL-11+CD4+ cells is significantly increased in CIS patients in comparison to healthy controls (HCs). Furthermore, we have identified IL-11 as a new Th17-promoting cytokine. IL-11 induces a differentiation of naïve CD4+ T cells into Th17 cells, as well as Th17 memory cell expansion, characterized by secretion of IL-17A, IL-17F, IL-21 and IL-22. Since the Th17 cytokines IL-17F, IL-21 and TNF- induced differentiation of naïve cells in the IL-11-secreting CD4+ cells, we propose that cross-talk between IL-11+CD4+ and Th17-cells may play a role in the initiation and propagation of the autoimmune response in RRMS. PBMCs were separated from 15 CIS patients and 7 HCs, and the total RNA was extracted and used for gene array hybridization as described previously. To detect differential gene expression profiles between the CIS patients and HCs, a two class paired test of significance analysis was used. In order to capture complex gene expression changes in the PBMCs derived from 15 CIS patients in comparison to 7 HCs, we performed a comprehensive study using Affymetrix Human Gene array U133 (HG-U133) with 45,000 probe sets representing approximately 33,000 human genes. The arrays were hybridized for 16 h at 45oC in a GeneChip® Hybridization Oven 640 (Affymetrix), washed and stained with R-phycoerythrin streptavidin in a GeneChip® Fluidics Station 400 (Affymetrix). The arrays were scanned with a Hewlett Packard GeneArray Scanner. Affymetrix GeneChip® Microarray Suite 5.0 software was used for washing, scanning, and basic analysis. To detect differential gene expression profiles between the CIS patients and HCs, a two class paired test of significance analysis of microarrays was used. Differentially expressed genes were determined using a Welch two sample t-test. A p<0.05 was considered significant.
2015-05-15 | E-GEOD-59085 | biostudies-arrayexpress
Project description:Activation of oncogenes often leads to induction of the DNA damage responses and onset of the cell senescence. Given that DNA damage can also trigger production of type I interferons (IFN) that contribute to senescence development, we sought to determine the role of IFN in the oncogene-induced senescence. Our data in mouse model demonstrate that inactivation of IFN signaling is sufficient for inducing melanomas in melanocytes harboring mutant Braf. Restoration of IFN signaling in IFN-deficient melanoma cells induces cell senescence and suppresses melanoma progression. In addition, data in human patients that received high dose IFN therapy and in mouse transplanted tumor models strongly suggest the importance of the non-cell-autonomous IFN signaling. Suppression of IFN signaling mediated by the downregulation of IFN receptor IFNAR1 invariably occurs during development of mouse melanoma. Mice harboring the IFNAR1 mutant, which is relatively resistant to downregulation, delay melanoma development, suppress the metastatic disease, and better respond to treatment with BRAF or PD1 inhibitors. These results suggest that IFN signaling is an important tumor suppressive pathway that inhibits melanoma development and progression. Accordingly, the inhibition of IFN pathway via IFNAR1 downregulation plays a key role in melanoma pathogenesis. Conversely, these data also argue for targeting IFNAR1 downregulation to prevent the metastatic disease and improve the efficacy of molecularly targeted and immune-targeted therapies. Two genotypes of mice were examined at 2 to 3 times after tamoxifen adminstration, with 2 replicates for each condition, yielding 8 samples in total.
2016-01-14 | E-GEOD-76842 | biostudies-arrayexpress
Project description:Transcriptome analysis of RNA samples from human PBMCs of IFN-beta treated multiple sclerosis patients. Interferon (IFN)-b-1a (Avonex) and longer half-life, polyethylene glycol-conjugated IFN-b-1a (PEG-IFN-b-1a, Plegridy), may generate different molecular responses. At 6 h, non-PEGylated IFN-b-1a injection upregulated expression of 136 genes and PEG-IFN-b-1a upregulated 85. At 24 h, induction was maximal; IFN-b-1a upregulated476 genes and PEG-IFN-b-1a now upregulated 598. Long-term PEG-IFN-b-1a therapy increased expression of antiviral and immune-regulatory genes (IFIH1, TLR8, IRF5, TNFSF10 [TRAIL], STAT3, JAK2, IL15, and RB1) and IFN signaling pathways (IFNB1, IFNA2, IFNG, IRF7), but downregulated expression of inflammatory genes (TNF, IL1B, and SMAD7). Long-term PEG-IFN-b-1a induced longer and stronger expression of Th1, Th2, Th17, chemokine, and antiviral proteins than long-term IFN-b-1a. Long-term therapy also primed the immune system, evoking higher gene and protein induction after IFN reinjection at 7 months than at 1 month of PEG-IFN-b-1a treatment. Both forms of IFN-b balanced correlations of expression among these genes and proteins, with positive correlations between Th1 and Th2 families, quelling the ‘‘cytokine storm’’ of untreated MS. Both IFNs induced long-term, potentially beneficial, molecular effects on immune and possibly neuroprotective pathways in MS.
2023-03-01 | GSE224351 | GEO
Project description:T cell differentiation to the Th17 effector subset requires stimulation through the T cell and co-stimulatory receptors, together with cytokine stimulation by TGFb and IL-6. The small molecule halofuginone (HF) inhibits Th17 cell development and induces a pattern of stress-regulated gene expression that mimics amino acid starvation. We used global transcript profiling to ask how halofuginone modulates gene expression induced during T cell activaiton and Th17 differentiation Experiment Overall Design: Purified mouse CD4+ CD25- T cells were activated under Th17 polarizing cytokine conditions and treated with either halofuginone or its inactive derivative, MAZ1310, for 3- or 6-hours.
2009-04-19 | E-GEOD-15624 | biostudies-arrayexpress
Project description:Our results introduce interleukin (IL)-11 as a new cytokine that may play a role in the development of the autoimmune response in patients with relapsing remitting multiple sclerosis (RR MS). IL-11 was found to be the highest up-regulated cytokine in the serum and cerebrospinal fluid (CSF) from patients with clinically isolated syndrome (CIS) suggestive of MS. It was also increased in the serum and CSF of patients with clinically definitive RRMS and during the clinical relapses of the disease. CD4+ cells represent a predominant cell source of IL-11 in the peripheral circulation, and the percentage of IL-11+CD4+ cells is significantly increased in CIS patients in comparison to healthy controls (HCs). Furthermore, we have identified IL-11 as a new Th17-promoting cytokine. IL-11 induces a differentiation of naïve CD4+ T cells into Th17 cells, as well as Th17 memory cell expansion, characterized by secretion of IL-17A, IL-17F, IL-21 and IL-22. Since the Th17 cytokines IL-17F, IL-21 and TNF- induced differentiation of naïve cells in the IL-11-secreting CD4+ cells, we propose that cross-talk between IL-11+CD4+ and Th17-cells may play a role in the initiation and propagation of the autoimmune response in RRMS. PBMCs were separated from 15 CIS patients and 7 HCs, and the total RNA was extracted and used for gene array hybridization as described previously. To detect differential gene expression profiles between the CIS patients and HCs, a two class paired test of significance analysis was used.
2015-05-15 | GSE59085 | GEO
Project description:Recently, hypoxia via the transcription factor HIF-1a has been implicated to play an important role for the fate of the adaptive immune response by regulatory T cells (Treg) and T helper 17 cells (TH17) in the mouse model. However, the reports on the effect of HIF-1a are conflicting and so far no functional data in the human system are available. Therefore, we analyzed the effect of hypoxia and HIF-1a on Treg and TH17 in the human system. FACS, western blot and reporter assays clearly demonstrated that hypoxia does not up-regulate the level of HIF-1a in CD4+ T cells (THC) and microarray analysis revealed no change of the transcriptome comparing normoxia vs. hypoxia. Furthermore, we could show that HIF-1a is almost exclusively regulated via NF-kB and NFAT, whereas hydroxylation and subsequent degradation of HIF-1a had little to no effect. In addition, we showed that HIF-1a is essential for nTreg mediated suppression and for IL-17A secretion of TH17, but not for TH17 lineage commitment measured by RORγt expression. In conclusion, our results demonstrated that THC have a distinct regulation of HIF-1a protein levels, which was absolutely essential for Treg and TH17 function. 3 patients, 2 cell type, 2 treatments = 12 arrays
2013-12-31 | E-GEOD-41999 | biostudies-arrayexpress
Project description:Recently, hypoxia via the transcription factor HIF-1a has been implicated to play an important role for the fate of the adaptive immune response by regulatory T cells (Treg) and T helper 17 cells (TH17) in the mouse model. However, the reports on the effect of HIF-1a are conflicting and so far no functional data in the human system are available. Therefore, we analyzed the effect of hypoxia and HIF-1a on Treg and TH17 in the human system. FACS, western blot and reporter assays clearly demonstrated that hypoxia does not up-regulate the level of HIF-1a in CD4+ T cells (THC) and microarray analysis revealed no change of the transcriptome comparing normoxia vs. hypoxia. Furthermore, we could show that HIF-1a is almost exclusively regulated via NF-kB and NFAT, whereas hydroxylation and subsequent degradation of HIF-1a had little to no effect. In addition, we showed that HIF-1a is essential for nTreg mediated suppression and for IL-17A secretion of TH17, but not for TH17 lineage commitment measured by RORγt expression. In conclusion, our results demonstrated that THC have a distinct regulation of HIF-1a protein levels, which was absolutely essential for Treg and TH17 function.
2013-12-31 | GSE41999 | GEO