IFNγ/IL10 ratio stratifies corticosteroids therapy for septic shock
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PROVIDER: PRJNA418303 | ENA |
REPOSITORIES: ENA
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Project description:To stratify hydrocortisone application in septic shock, we investigated an immune sub-study of the CORTICUS trial (Sprung et.al 2008, NEJM) employing machine learning to a panel of 120 parameters of 84 patients (n=24 non-survived, n=60 survived, 28 days) with special emphasis on potentially disadvantageous corticosteroids effects in the context of sepsis including clinical parameters, organ failure scores, lymphocyte counts and plasma protein concentrations of cytokines. We identified the ratio of IFNγ/IL10 in serum before randomization to serve as a valid biomarker for treatment stratification. This was validated with cytokine serum levels of patients (n=49) from the SISPCT study (Bloos et.al 2016, JAMA) and the early arm (n=20) of a hydrocortisone cross-over study (Keh et.al. 2003, Am J Respir Crit Care Med). Integrating these three studies, we yielded an odds ratio of 2.1 and a 95% confidence interval of 0.99-4.52 (P=0.03).In vitro assays revealed IFNγ/Il10 to reflect the burden or severity of systemic infection. Severity was evidencedbyserum levels of these cy-tokines in the patients with septic shock we observed, and also in patients with less severe sepsis. Elucidating the molecular regulation of leukocytes during treatment and placebo by a transcriptomics analysis pointed to induced recovery of immune cell function due to hydro-cortisone treatment, particularly in the predicted hydrocortisone responders. IFNγ/IL10 is a molecular marker with high potential for support of hydrocortisone therapy decision. IFNγ/IL10 is reasonable for this as it reflects the burden and recovery of the immune system which seems to be indicative for corticosteroids treatment of septic shock.
2019-10-01 | GSE106878 | GEO
Project description:The cytokine IFNγ differentially impacts on tumors upon immune checkpoint blockade (ICB). Despite our understanding of downstream signaling events, less is known about 36 regulation of its receptor (IFNγ-R1). With an unbiased genome-wide CRISPR/Cas9 screen for critical regulators of IFNγ-R1 cell surface abundance, we identified STUB1 as an E3 ubiquitin ligase for IFNγ-R1 in complex with its signal-relaying kinase JAK1. STUB1 mediates ubiquitination-dependent proteasomal degradation of IFNγ-R1/JAK1 complex through IFNγ-R1K285 and JAK1K249. Conversely, STUB1 inactivation amplifies IFNγ signaling, sensitizing tumor cells to cytotoxic T cells in vitro. This was corroborated by an anticorrelation between STUB1 expression and IFNγ response in ICB-treated patients. Consistent with the context-dependent effects of IFNγ in vivo, anti-PD-1 response was increased in heterogenous tumors comprising both wildtype and STUB1-deficient cells but not full STUB1 knockout tumors. These results uncover STUB1 as a critical regulator of IFNγ-R1, and highlight the context-dependency of STUB1-regulated IFNγ signaling for ICB outcome.
2022-03-07 | PXD030580 | Pride
Project description:chromatin accessibility (ATAC-seq) experiment. HeLa cells were primed with IFNγ for 24 hours, followed by IFNγ washout. After 48h, naïve and primed cells were induced by IFNγ for 1h and 3h. Cells were harvested at indicated time points and processed for ATAC-seq.
2023-05-06 | E-MTAB-12624 | biostudies-arrayexpress
Project description:Prenatal exposure to synthetic corticosteroids can significantly alter postnatal development through changes in neurotransmitters and their receptors, and thus having long-lasting behavioral effects. Some of these changes have been observed in animal experiments, others also in humans prenatally exposed to synthetic corticosteroids. Here, we focused on transcriptomic changes within the prefrontal cortex of female rats prenatally exposed to either betamethasone or saline. The transcriptome has been assessed by novel computational tools to determine complex changes that may have life-long effects on phenotype, i.e., behavior. We analyzed how composition, topology and modulatory networks of the genomic fabric of the dopaminergic, GABAergic, and glutamatergic synapse (the transcriptome of the most interconnected and stably expressed gene network responsible for specific transmission) are afected by the prenatal exposure to corticosteroids and postnatal ketamine-induced seizures. One sex (F) x two prenatal exposures (B = betamethasone, S = saline) x two postnatal treatments (K = ketamine, S = saline). Biological replicates: 4 FSS, 4 FBS, 4 FBK.
2016-01-09 | E-GEOD-76694 | biostudies-arrayexpress
Project description:Despite its success, immune checkpoint blockade (ICB) cannot induce durable responses in most patients. This is partially attributed to reduced sensitivity to interferon gamma (IFNγ). Thus, elevating tumor IFNγ-receptor 1 (IFNγ-R1) expression to enhance IFNγ-mediated cytotoxicity is of clinical interest. Here, we demonstrate higher IFNγ-R1 expression to sensitize tumors to IFNγ-mediated killing. To unveil the largely undefined mechanisms of IFNγ-R1 expression, we performed a genome-wide CRISPR/Cas9 knockout screen for suppressors of IFNγ-R1 tumor cell surface abundance. We uncovered STUB1 as key mediator for proteasomally degrading IFNγ-R1/JAK1 complex. Conversely, STUB1 inactivation in tumor cells amplified IFNγ signaling and sensitized to cytotoxic T cells, but permitted IFNγ-induced PD-L1 expression. Rationally combining STUB1 inactivation with anti-PD-1 treatment effectively eliminated tumors in vivo. Clinically corroborating this is a STUB1 transcriptomic signature that associates with response to anti-PD-1 treatment in two patient cohorts. Thus, uncovering STUB1 as a pivotal regulator of IFNγ signaling and a synergistic target for anti-PD-1 treatment.
2022-02-24 | GSE154040 | GEO
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2023-05-06 | E-MTAB-12625 | biostudies-arrayexpress
Project description:For comparison of the transcription profile between IFNγ-PD-L1all and IFNγ+PD-L1all cells, we treated KPC1199 cells with vehicle control or 10 ng/mL recombinant mouse IFNγ for 20 hours and harvested them. For comparison of PD-L1hi with PD-L1all, cells were either sorted with the top 15% PD-L1+ or total of IFNγ+PD-L1all PDAC cells, and freshly collected as soon as possible to be used for RNA preparation.
2024-08-20 | GSE222222 | GEO
Project description:Abstract: Interleukin-10-deficient (Il10-/-) mice serve as a model for inflammatory bowel disease (IBD). The severity of colitis strongly depends on the inbred strain carrying the disrupted Il10 gene: C3H/HeJBir (C3) confers disease susceptibility, whereas C57BL/6J (B6) confers resistance. Genome-wide scans with microsatellite markers on segregrating backcross and F2 populations resulted in the detection of ten colitogenic quantitative trait loci (QTL). The aim of this study was to reduce the large number of candidate genes within the QTL intervals by identifying those genes which are located within the candidate gene intervals and which are differentially expressed in the colon of IBD-susceptible and -resistant strains. Using this combination of QTL mapping and microarray analysis, we identified 16 genes which were differentially expressed between B6- and C3-Il10-/- mice and were located within the candidate gene intervals. Three of these genes (Pla2g2a, Gbp1, Cd14) showed prominent differences in expression levels between B6- and C3-Il10-/- as well as between B6 and C3 wildtype mice and were considered to be major candidate genes. Pla2g2a and Gbp1 are known to be polymorphic between C3 and B6 mice. Expression data for Cd14 were confirmed by real-time RT PCR using specified pathogen free and germfree Il10-/- mice. In conclusion, the large number of candidate genes was reduced to three major candidates by using a combination of QTL mapping and microarray analysis. All three genes play an important role in inflammatory processes and immune response. Material & Methods: Two independent microarray experiments were performed using SPF mice: 19 for the first experiment (4 C3 WT [GSM39296], 5 C3-Il10-/- [GSM39297], 5 B6 WT [GSM39290], 5 B6-Il10-/- [GSM39291]) and 18 for the second (4 C3 WT [GSM39295], 4 C3-Il10-/- [GSM39294], 5 B6 WT [GSM39288], 5 B6-Il10-/- [GSM39289]). The mice were euthanized by cervical dislocation. Following a ventral midline incision, the colon (including the rectum, but not the anus) was removed and flushed with PBS. Each colon was opened longitudinally with a pair of scissors, further dissected and homogenized using a micropistill in 1.5 ml peqGOLD Trifast FL. RNA was isolated according to the manufacturer´s protocol, and quality was checked using RNA Nano LabChip® technology (Agilent, Böblingen, Germany). For each of the two array experiments, equal amounts (7 micro gram) of RNA were pooled from the four or five animals of each mouse strain, resulting in a total of eight samples. For biotin-labeled target synthesis starting from 3-5 µg of total RNA, reactions were performed using standard protocols supplied by the manufacturer (Affymetrix; Santa Clara, CA). Briefly, 3-5 µg total RNA were converted to dsDNA using 100 pmol of a T7T23V primer (Eurogentec; Seraing, Belgium) containing a T7 promoter. The cDNA was then used directly in an in-vitro transcription reaction in the presence of biotinylated nucleotides. The concentration of biotin-labeled cRNA was determined by UV absorbance. In all cases, 12.5 µg of each biotinylated cRNA preparation were fragmented and placed in a hybridization cocktail containing four biotinylated hybridization controls (BioB, BioC, BioD, and Cre) as recommended by the manufacturer. Samples were hybridized to an identical lot of Affymetrix MG U74Av2 for 16 hours. Data selection and transformation procedures. For normalization, all array experiments were scaled to a target intensity of 150, otherwise using the default values of the Microarray suite 5.0 (MAS 5.0). Filtering of the results was done as follows: Genes were considered as strong regulated if their fold change was greater than or equal 2 or less than or equal -2, the statistical parameter for a significant change was less than 0.01 (change p-Value for changes called Increased) or greater than 0.99 (change p-Value for changes called Decreased). Additionally, the signal difference of a certain gene was greater than 200. Genes were considered as weak regulated if their fold change was greater than or equal 1.5 or less than or equal -1.5, the statistical parameter for a significant change was less than 0.001 or greater than 0.999 and the signal difference of a certain gene was greater than 40. Keywords = Inflammatory Bowel Disease Keywords = IBD Keywords = interleukin-10 Keywords = microarray Keywords = mice Keywords = quantitative trait locus Keywords = QTL Keywords = susceptibility Keywords: parallel sample
2005-12-31 | GSE2172 | GEO
Project description:IL10 mouse gut bacterial communities
| PRJNA909836 | ENA
Project description:Prenatal exposure to synthetic corticosteroids can significantly alter postnatal development through changes in neurotransmitters and their receptors, and thus having long-lasting behavioral effects. Some of these changes have been observed in animal experiments, others also in humans prenatally exposed to synthetic corticosteroids. Here, we focused on transcriptomic changes within the prefrontal cortex of female rats prenatally exposed to either betamethasone or saline. The transcriptome has been assessed by novel computational tools to determine complex changes that may have life-long effects on phenotype, i.e., behavior. We analyzed how composition, topology and modulatory networks of the genomic fabric of the dopaminergic, GABAergic, and glutamatergic synapse (the transcriptome of the most interconnected and stably expressed gene network responsible for specific transmission) are affected by prenatal exposure to corticosteroids and postnatal ketamine/saline treated NMDA-induced seizures.
2016-01-09 | GSE76694 | GEO