Prolonged Interferon-Stimulated Gene and Protein Signatures in Multiple Sclerosis Induced by PEGylated IFN-beta-1a Compared to Non-PEGylated IFN-beta-1a
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PROVIDER: PRJNA930700 | ENA |
REPOSITORIES: ENA
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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:The purpose of this study was to characterize the transcriptional effects induced by subcutaneous IFN-beta-1a treatment (Rebif, 22 µg or 44 µg three times a week) in patients with relapsing-remitting form of multiple sclerosis (MS). By using Affymetrix DNA microarrays, we obtained genome-wide expression profiles of peripheral blood mononuclear cells from 12 MS patients within the first two years of IFN-beta administration.
2011-12-06 | GSE33464 | GEO
Project description:The purpose of this study was to characterize the transcriptional effects induced by subcutaneous IFN-beta-1a treatment (Rebif, 22 µg or 44 µg three times a week) in patients with relapsing-remitting form of multiple sclerosis (MS). By using Affymetrix DNA microarrays, we obtained genome-wide expression profiles of peripheral blood mononuclear cells from 12 MS patients within the first two years of IFN-beta administration. EDTA blood samples were taken from all patients immediately before first and second IFN-beta injection as well as after 1 month, 1 year and 2 years. Total RNA of Ficoll-isolated peripheral blood mononuclear cells from each sample was extracted, labeled and hybridized to Affymetrix Human Genome U133 Plus 2.0 arrays to quantify the mRNA levels. This GEO entry provides the U133 Plus 2.0 microarray data.
2011-12-06 | E-GEOD-33464 | biostudies-arrayexpress
Project description:Interferon (IFN) beta-1a is an approved treatment for relapsing remitting multiple sclerosis (RRMS) and has been examined for use in secondary progressive multiple sclerosis (SPMS). However, no information regarding blood transcriptional changes induced by IFN treatment in SPMS patients is available. Our aim was to identify a subgroup of SPMS patients presenting a gene expression signature similar to that of RRMS patients who are clinical responders to IFN treatment.
2015-10-06 | GSE73608 | GEO
Project description:The purpose of this study was to characterize the transcriptional effects induced by intramuscular IFN-beta-1a treatment (Avonex, 30 µg once weekly) in patients with relapsing-remitting form of multiple sclerosis (MS). By using Affymetrix DNA microarrays, we obtained genome-wide expression profiles of peripheral blood mononuclear cells from 24 MS patients within the first four weeks of IFN-beta administration. Keywords: Multiple sclerosis, Interferon, Pharmacogenomics, Affymetrix
2009-12-03 | GSE19285 | GEO
Project description:A single high dose of IFN? activates powerful cellular responses in which many antiviral, pro-apoptotic, and anti-proliferative proteins are highly expressed. Since some of these proteins are deleterious, cells down-regulate this initial response rapidly. However, the expression of many antiviral proteins that do no harm is sustained, prolonging a substantial part of the initial antiviral response for days and also providing resistance to DNA damage. While the transcription factor ISGF3 (IRF9 and tyrosine-phosphorylated STATs 1 and 2) drives the first rapid response phase, the related factor un-phosphorylated ISGF3 (U-ISGF3), formed by IFN?-induced high levels of IRF9 and STATs 1 and 2 without tyrosine phosphorylation, drives the second prolonged response. The U-ISGF3-induced antiviral genes that show prolonged expression are driven by distinct interferon stimulated response elements (ISREs). Continuous exposure of cells to a low level of IFN?, often seen in cancers, leads to steady-state increased expression of only the U-ISGF3-dependent proteins, with no sustained increase of other IFN?-induced proteins, and to constitutive resistance to DNA damage. We classified genes into U-ISGF3-induced genes and classical ISGF3-induced genes using microarray data. We identified 150 genes that are up-regulated by IFN? after 6 h. Among these IFN?-induced genes, only 29 (20%) were induced by the up-regulation of Y701F-STAT1, indicating that these are induced by U-ISGF3. Among the remaining 121 IFN?-induced genes (150 minus 29), 73 are induced by IFN? as well as IFN?, and 48 are induced only by IFN?. Total 5 RNA samples were analyzed in duplicate on microarray chips. Untreated cells and empty vector-transfected cells were the control of IFN treated cells and Y701F-STAT1-transfected cells, respectively.
2013-09-18 | E-GEOD-50954 | biostudies-arrayexpress
Project description:Glioma cells are sensitized to the alkylator temozolomide after exposure to IFN-beta. In glioma-initiating cells (GIC), IFN-beta alone reduces clonogenicity. We investigated differentially expressed genes with or without IFN exposure in either longterm glioma cells or GIC. We used microarrays to investigate differential gene regulation in glioma cells after exposure to either ddH20 or IFN-beta 300 IU/ml at 6 h or 24 h. We used either the longterm cell line LNT-229 or the GIC cell lines GS-2 and GS-9 and exposed them to either IFN-beta 300 IU/ml or ddH20 for 6 h or 24 h.
2014-03-31 | E-GEOD-53213 | biostudies-arrayexpress
Project description:We aimed to identify specific biomarkers of IFN-beta bioactivity in order to compare their gene expression induction by type I IFNs with the MxA, and to investigate their potential role in MS pathogenesis. Gene expression microarrays were performed in PBMC from MS patients who developed neutralizing antibodies (NAB) to IFN-beta. Nine genes followed patterns in gene expression over time similar to the MX1 and were selected for further experiments: IFI6, IFI27, IFI44L, IFIT1, HERC5, LY6E, RSAD2, SIGLEC1, and USP18. In vitro experiments revealed specific induction of selected biomarkers by IFN-beta but not IFN-gamma, and several markers, in particular USP18 and HERC5, were significantly induced at lower IFN-beta concentrations and more selective than the MX1 as biomarkers of IFN-beta bioactivity. In addition, USP18 expression was deficient in MS patients compared with healthy controls (p=0.0004). We propose specific biomarkers that may be considered in addition to the MxA to evaluate IFN-beta bioactivity, and to further explore their implication in MS pathogenesis. Number of samples: 32. We analyzed PBMC from 8 patients at baseline and after 3, 12 and 24 months of IFN-beta treatment
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Project description:IFNβ, an effective therapy against relapsing-remitting (RR) multiple sclerosis (MS) is naturally secreted during the innate immune response against viral pathogens. The objective of this study was to characterize the immunomodulatory mechanisms of IFNβ targeting innate immune response and their effects on DC-mediated regulation of T-cell differentiation. We found that IFNβ−1a in-vitro treatment of human monocyte-derived dendritic cells (DCs) induced the expression of TLR7 and the members of its downstream signaling pathway, including myeloid differentiation factor 88 (MyD88), IL-1R-associated kinase (IRAK)4, and TNF receptor-associated factor (TRAF)6, while it inhibited the expression of IL-1R. Using siRNA TLR7 gene silencing, we confirmed that IFNβ-1a-induced changes in MyD88, IRAK4 and IL-1R expression were dependent on TLR7. TLR7 expression was also necessary for the IFNβ-1a-induced inhibition of IL-1β and IL-23, and the induction of IL-27 secretion by DCs. Supernatant (SN) transfer experiments confirmed that IFNβ-1a-induced changes in DCs’ cytokine secretion inhibit Th17 cell differentiation as evidenced by the inhibition of retinoic acid-related orphan nuclear hormone receptor C (RORC) and IL-17A gene expression and IL-17A secretion. Our study has identified a novel therapeutic mechanism of IFNβ−1a, that selectively targets the autoimmune response in MS. Keywords: The effect of IFN beta-1a on the gene expression in patients with clinically isolated syndrome suggestive of MS
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Project description:We studied the gene expression patterns in PBMC from relapsing remitting MS patients undergoing weekly IFN-ß-1a therapy. On the basis of two fold changes in expression levels and statistical analyses we selected a diagnostic set of 137 genes that were differentially expressed between pretreatment and IFN-ß-1a-treated MS patients. Some these 137 genes may provide the basis for lack of IFN-ß-1a response. Keywords: Drug response to Interferon beta therapy in Multiple Sclerosis patients.
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