Impact of MEM40 and IFNB on human DC activation markers
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE223342 | GEO | 2023/02/13
REPOSITORIES: GEO
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Project description:This experiment set is used for the manuscript entitled: Pharmacogenomics of Interferon-b therapy in multiple sclerosis: Baseline IFN signature determines pharmacological differences between patients. In this study we generated and analyzed pre- and post- IFNb treatment gene expression patterns of RRMS patients with the aim of identifying pre-existing and/or drug-induced signatures that will allow us to make predictions on the expected pharmacological effects of IFNb treatment. We show that the expression level of IFN response genes prior to treatment, determines the pharmacological differences between patients with MS at the molecular level. A group of 16 Dutch patients (10 females and 6 males) with clinically definite relapsing-remitting MS was recruited from the outpatient clinic of the MS Centre Amsterdam. Mean age at start of IFNb therapy is 40.6 +/- 7.7, mean EDSS is 2.3 +/- 1.3 (range 1-6). Blood samples were obtained just before treatment and 1 month after start of the therapy. Patients received Avonex, Betaferon, Rebif 22 or Rebif 44. A compound treatment design type is where the response to administration of a compound or chemical (including biological compounds such as hormones) is assayed. Compound Based Treatment: Before and 1 month after IFNb therapy Keywords: compound_treatment_design
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Project description:DC-SIGN+ monocyte-derived dendritic cells (mo-DCs) play important roles in bacterial infections and inflammatory diseases, but the factors regulating their differentiation and proinflammatory status remain poorly defined. Here, we identify a micro-RNA, miR-181a, and a molecular mechanism that simultaneously regulate the acquisition of DC-SIGN+ expression and the activation state of DC-SIGN+ mo-DCs. Specifically, we show that miR-181a promotes DC-SIGN expression during terminal mo-DC differentiation and limits its sensitivity and responsiveness to TLR triggering and CD40 ligation. Mechanistically, miR-181a sustains ERK-MAPK signaling in mo-DCs, thereby enabling the maintenance of high levels of DC-SIGN and a high activation threshold. Low miR-181a levels during mo-DC differentiation, induced by inflammatory signals, do not support the high phospho-ERK signal transduction required for DC-SIGNhi mo-DCs and lead to development of proinflammatory DC-SIGNlo/- mo-DCs. Collectively, our study demonstrates that high DC-SIGN expression levels and a high activation threshold in mo-DCs are linked and simultaneously maintained by miR-181a.
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Project description:Impact of MEM40 and IFNB on human DC activation markers
| PRJNA925839 | ENA
Project description:This experiment set is used for the manuscript entitled: Pharmacogenomics of Interferon-b therapy in multiple sclerosis: Baseline IFN signature determines pharmacological differences between patients. In this study we generated and analyzed pre- and post- IFNb treatment gene expression patterns of RRMS patients with the aim of identifying pre-existing and/or drug-induced signatures that will allow us to make predictions on the expected pharmacological effects of IFNb treatment. We show that the expression level of IFN response genes prior to treatment, determines the pharmacological differences between patients with MS at the molecular level. A group of 16 Dutch patients (10 females and 6 males) with clinically definite relapsing-remitting MS was recruited from the outpatient clinic of the MS Centre Amsterdam. Mean age at start of IFNb therapy is 40.6 +/- 7.7, mean EDSS is 2.3 +/- 1.3 (range 1-6). Blood samples were obtained just before treatment and 1 month after start of the therapy. Patients received Avonex, Betaferon, Rebif 22 or Rebif 44. A compound treatment design type is where the response to administration of a compound or chemical (including biological compounds such as hormones) is assayed. Compound Based Treatment: Before and 1 month after IFNb therapy Keywords: compound_treatment_design Complex
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Project description:Lyme disease is caused by infection with Borrelia burgdorferi, with a spectrum of clinical disorders. Murine studies with B6 and C3H mice have demonstrated that genetic differences in the host response play an essential role in regulating the severity of Lyme arthritis. C3H mice generate a robust induction of type I IFN response in joint tissue at one week of infection which leads to severe Lyme arthritis at 4 weeks post-infection, while B6 mice develop mild disease without a type I IFN profile. We used a forward genetic approach and identified B. burgdorferi arthritis- associated locus 1 (Bbaa1) on Chr4, which includes type I IFN cluster. B6.C3-Bbaa1 congenic mice display more severe Lyme arthritis than B6 mice. The blocking of type I IFN receptor and the IFNb subtype in Bbaa1 mice suppressed arthritis back to B6 level, so we concluded the Bbaa1 locus intrinsically controls IFNb production, and the differential expression of IFNb controls the severity of Lyme arthritis. However, the IFNb genes of C3H and B6 mice are identical, prompting focus on other genetic factors within the Bbaa1 locus as regulators of IFNb. Reciprocal radiation chimeras between B6.C3-Bbaa1 and B6 mice revealed myeloid cells in the joint tissue as IFNb initiators. Advanced congenic lines were generated to reduce the genetic contribution from C3H Bbaa1 region. RNA-seq of bone marrow-derived macrophages (BMDMs) from B6 and advanced interval specific recombinant congenic lines, ISRCL3 and ISRCL4, revealed novel candidates that may regulate Ifnb. In this study, we identify the Cdkn2a gene encoded ARF as a critical regulator of IFNb mediated Lyme arthritis, and investigate mechanistic interactions that modulate IFNb expression in Lyme arthritis development.
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Project description:Bone marrow (BM) cells derived from femurs of C57BL/6 mice were used to generate BM-DCs. For this, BM cells (2x106 cells/10 ml) were seeded on 100 mm2 bacterial dishes (Greiner bio-one, Frickenhausen, Germany). DC culture media (IMDM, 5% [v/v] FCS [PAA, Coelbe, Germany], 100 U/ml penicillin, 100 ug/ml streptomycin [both Gibco, Paisly, UK], 50 uM beta-mercaptoethanol [Roth, Karlsruhe, Germany] 5% [v/v] of murine GM-CSF containing cell culture supernatant was replenished on days 3 and 6 of culture. Aliquots of DC cultures were treated with recombinant human 100 ng/ml WNT-1 (Biovision, Milpitas, CA) for 48h on days 7 or 8 of culture. Each 20 ug of total RNA derived from unstimulated BM-DCs treated for 48 h with WNT-1 (100 ng/ml) or left untreated was used for generation of fluorescecne-labeled cDNA probes (Alexa Fluor 555-aha-dUTP for untreated BM-DCs; Alexa Fluor 647-aha-dUTP for WNT-treated BM-DCs). <br><br><br><br>Prehybridized (5X SSPE,0.1% SDS, and 1% BSA) microarrays (Mouse Whole Genome OneArray Microarray v2; Phalanx Biotech, San Diego, U.S.A.) were hybridized with each 20 pmol of either fluorescence-labeled cDNA probe using OneArray Hybridization Buffer with 18% formamide for 16 h (Lucidea SlidePro Hybridizer; GE Healthcare, Munich, Germany) according to the OneArray hybridization protocol. Washed microarrays were analysed using a ScanArray 4000 system equipped with ScanArray 4.0 software (both Perkin-Elmer; Rodgau-Jugesheim, Germany) at 10 pixel size. Laser intensity (90-100%) and photomultiplier tube sensitivity (60-70%) were varied to optimize signal to background ratios. Derived images weere analyzed using the ScanArray 4.0 easyquant software module. Intensity data were normalized (loess normalization; MIDAS-2.19) and subjected to significance analysis (MEV 4.3) using appropriate modules of the TM4 microarray software suite. Changes in gene expression with p < 5% were used for subsequent analyses. Gene ontology annotations were performed with Panther software (Thomas et al., 2003).
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