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Unknown,Transcriptomics,Genomics,Proteomics

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Transcription profiling of human Sez-4 cell line starved of IL2 for 16h, followed by addition of IL-2 activation and or JAK inhibition

ABSTRACT: In this study we compared the effects of IL-2, IL-15, and IL-21 on the gene expression, activation of cell signaling pathways, and functional properties of cells derived from the CD4+ cutaneous T-cell lymphoma (CTCL). Whereas both IL-2 and IL-15 that signal through receptors that share the common gamma chain and the beta chain modulated the expression of >1,000 genes, IL-21 that signals via the receptor also containing gamma chain up-regulated <40 genes. All three cytokines induced tyrosine phosphorylation of Jak1 and Jak3. However, only IL-2 and IL-15 strongly activated STAT5, PI3K/Akt, and MEK/ERK signaling pathways. In contrast, IL-21 selectively activated STAT3. Whereas all three cytokines protected CTCL cells from apoptosis, only IL-2 and IL-15 promoted their proliferation. The effects of the cytokine stimulation were Jak3- and Jak1-kinase dependent. These findings document the vastly different impact of IL-2 and IL-15 vs. IL-21 on malignant CD4+ T cells. They also suggest two novel therapeutic approaches to CTCL and, possibly, other CD4+ T cell lymphomas: inhibition of the Jak1/Jak3 kinase complex and, given the known strong immunostimulatory properties of IL-21 on CD8+ T, NK, and B cells, application of this cytokine to boost an immune response against malignant CD4+ T cells. Experiment Overall Design: Sez-4 cell line was starved of IL-2 for 16h, washed twice and placed into 6-well plates in 10ml RPMI (10% FBS) for 2h followed by pre-treating for 30â?? with pan-Jak inhibitor (300 nM), Jak3 inhibitor (300 nM), or drig solvent and cultured with IL-2 (200U) or medium alone for 4 h.

ORGANISM(S): Homo sapiens

SUBMITTER: Mariusz Wasik

PROVIDER: E-GEOD-8687 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Transcription profiling of human CD4+ cutaneous T-cell lymphoma (CTCL) Sez-4 cell line activated with IL-2, IL-15 or IL-21.

Project description:In this study we compared the effects of IL-2, IL-15, and IL-21 on the gene expression, activation of cell signaling pathways, and functional properties of cells derived from the CD4+ cutaneous T-cell lymphoma (CTCL). Whereas both IL-2 and IL-15 that signal through receptors that share the common gamma chain and the beta chain modulated the expression of >1,000 genes, IL-21 that signals via the receptor also containing gamma chain up-regulated <40 genes. All three cytokines induced tyrosine phosphorylation of Jak1 and Jak3. However, only IL-2 and IL-15 strongly activated STAT5, PI3K/Akt, and MEK/ERK signaling pathways. In contrast, IL-21 selectively activated STAT3. Whereas all three cytokines protected CTCL cells from apoptosis, only IL-2 and IL-15 promoted their proliferation. The effects of the cytokine stimulation were Jak3- and Jak1-kinase dependent. These findings document the vastly different impact of IL-2 and IL-15 vs. IL-21 on malignant CD4+ T cells. They also suggest two novel therapeutic approaches to CTCL and, possibly, other CD4+ T cell lymphomas: inhibition of the Jak1/Jak3 kinase complex and, given the known strong immunostimulatory properties of IL-21 on CD8+ T, NK, and B cells, application of this cytokine to boost an immune response against malignant CD4+ T cells. Experiment Overall Design: Sez-4 cell line was starved of IL2 for 16h, washed twice and placed into 6-well plates in 10ml RPMI (10% FBS) for 2 h followed by addition of IL-2 (200U), IL-15 (20ng/mL), or IL-21 (100 ng/ml) or medium alone for 4 h.

2008-04-09 | E-GEOD-8685 | biostudies-arrayexpress

Activation of Sez-4 cell line with IL-2, IL-15 or IL-21.

2008-02-19 | GSE8685 | GEO

Inhibition of activation of Sez-4 cell line with IL-2 by Jak kinase inhibitors.

2008-02-19 | GSE8687 | GEO

Effect of a JAK inhibitor on gene expression of HUT78 cell line

Project description:Developing targeted therapy for cutaneous T cell lymphoma (CTCL) patients still requires actionable mutated genes and deregulated pathways to be identified. There is increasing evidence that activating mutations in JAK genes and deregulated JAK/STAT signaling are important mechanisms involved in multiple B and T cell malignancies, including CTCL. Therefore, in this study we focused on studying the mutational status of JAK1, JAK2 and JAK3 genes in a series of human CTCL lesions and cell lines using next-generation sequencing (NGS). We found that 7 of 48 (14.7%) of the analyzed cases harbored mutations in the JAK1 and JAK3 genes that mainly affected the pseudokinase domain of the corresponding proteins. On the basis of these results, we used a specific JAK inhibitor (INCB018424) in a series of CTCL cell lines with deregulated JAK/STAT activity. Treatment of CTCL cells with INCB018424 resulted in dose-dependent reduction of activated STAT expression, diminished cell viability, and increased apoptosis. We also studied global changes in gene expression in cells with mutated JAK1 and JAK3 proteins treated with INCB018424 and identified multiple genes that were differentially regulated by JAK/STAT signaling, such as FGF20 (upregulated) and EGR1 (downregulated). Thus, our results show that the detection of deregulated JAK/STAT signaling in CTCL lesions via JAK mutations or other surrogate markers may serve to indicate the clinical use of JAK/STAT inhibitors. 3 replicates of cells treated with DMSO or JAKi during 30 min and 3h

2015-10-31 | E-GEOD-68562 | biostudies-arrayexpress

Effect of a JAK inhibitor on gene expression of HUT78 cell line

2015-10-31 | GSE68562 | GEO

Genome-wide detection of STAT6 binding sites in IL-4 treated naive human CD4+ T cells

Project description:STAT6 is a major transcription factor driving the polarization of Th2 cells in response to IL-4. STAT6 is phosphorylated by Jak1 and Jak3 kinases at the IL-4 receptor, after which phosphorylated STAT6 forms a homodimer and translocates into the nucleus. There STAT6 binds to specific DNA sequences, regulating the transcription of its target genes. Here we have analyzed on a genome wide level the STAT6 binding sites, after 1h and 4h of IL-4 induction, in naive human CD4+ T cells. Keywords: SRA Altogether 5 samples from 1 biological replicate were analyzed. Activated and IL-4 treated samples were compared to only activated or untreated samples to identify unique STAT6 binding sites after IL-4 induction.

2010-06-25 | E-GEOD-17850 | biostudies-arrayexpress

Genome-wide detection of STAT6 binding sites in IL-4 treated naive human CD4+ T cells

2010-06-25 | GSE17850 | GEO

IL-21-mediated non-canonical pathway for IL-1? production in conventional dendritic cells

Project description:The canonical pathway for IL-1? production requires TLR-mediated NF-?B-dependent Il1b gene induction, followed by caspase-containing inflammasome-mediated processing of pro-IL-1?. Here we show that IL-21 unexpectedly induces IL-1? production in conventional dendritic cells (cDCs) via a STAT3-dependent but NF-?B-independent pathway. IL-21 does not induce Il1b expression in CD4+ T cells, with differential histone marks present in these cells versus cDCs. IL-21-induced IL-1? processing in cDCs does not require caspase-1 or caspase-8 but depends on IL-21-mediated death and activation of serine protease(s). Moreover, STAT3-dependent IL-1? expression in cDCs at least partially explains the IL-21-mediated pathologic response occurring during infection with Pneumonia Virus of Mice. These results demonstrate lineage-restricted IL-21-induced IL-1? via a non-canonical pathway and provide evidence for its importance in vivo. Genome-wide transcription factors mapping and binding of STAT3, H3K4me3, H3K27me, H3K4me1, H3K27ac in mouse CD4+ T cells and dendritic cells in WT and Stat3-/- mice. RNA-Seq is performed in mouse CD4+ T cells and dendritic cells in WT mice, with or without indicated cytokines.

2015-07-07 | E-GEOD-61677 | biostudies-arrayexpress

Effect of JAK1/3 blockade on IL2 response in NK cells

2016-07-20 | GSE84562 | GEO

Effect of JAK1/3 blockade on IL2 response in NK cells

Project description:IL2 signals are transmitted through JAK1 and JAK3, but the transcriptomic consequences of each to the overall response is unclear. Here we analyzed the relative contribution of JAK1 and JAK3 to the NK cell IL2 response in vitro using titrated doses of isoform specific JAK inhibitors. Blockade of JAK1 and JAK3 have unequal effects on IL2-induced transcripts at pharmacologically relevant doses. Splenic NK cells were isolated by negative selection from 6wk old male C57BL/6 mice. These were cultured with IL2 (250U/ml) in the presence or absence of JAK1/3 inhibitors for 8hrs in vitro. Cells were then transferred directly into TriZol. RNA was prepared in Trizol for gene expression profiling by Affymetrix Mouse Gene 1.0 ST Arrays.

2016-07-20 | E-GEOD-84562 | biostudies-arrayexpress

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