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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE84562 | GEO | 2016/07/20

SECONDARY ACCESSION(S): PRJNA329657

REPOSITORIES: GEO

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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

Selective inhibitors of JAK1 targeting a subtype-restricted allosteric cysteine

Project description:The JAK family of non-receptor tyrosine kinases includes four subtypes (JAK1, JAK2, JAK3, and TYK2) and is responsible for signal transduction downstream of diverse cytokine receptors. JAK inhibitors have emerged as important therapies for immuno(onc)ological disorders, but their use is limited by undesirable side effects presumed to arise from poor subtype selectivity, a common challenge for inhibitors targeting the ATP-binding pocket of kinases. Here, we describe the chemical proteomic discovery of a druggable allosteric cysteine present in the non-catalytic pseudokinase domain of JAK1 (C817) and TYK2 (C838), but absent from JAK2 or JAK3. Electrophilic compounds selectively engaging this site block JAK1-dependent transphosphorylation and cytokine signaling, while appearing to act largely as “silent” ligands for TYK2. Importantly, the allosteric JAK1 inhibitors do not impair JAK2-dependent cytokine signaling and are inactive in cells expressing a C817A JAK1 mutant. Our findings thus reveal an allosteric approach for inhibiting JAK1 with unprecedented subtype selectivity.

2023-07-20 | PXD031384 | Pride

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

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 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.

2008-04-09 | E-GEOD-8687 | biostudies-arrayexpress

Selective inhibition of JAK1 with filgotinib reverses pathogenic processes in the DSS preclinical model for IBD

Project description:The pathogenesis of inflammatory bowel diseases (IBD) is associated with a dysregulated mucosal immune response. The signaling of several cytokines regulating this immune response is mediated by kinases of the JAK family, i.e. JAK1, JAK2, JAK3 and TYK2. Filgotinib is a JAK1-selective inhibitor with demonstrated efficacy in phase 2 trials in patients with rheumatoid arthritis (RA) and Crohn’s disease (CD). Here, we investigated the effects of filgotinib on the DSS (dextran sulfate sodium) mouse model

2020-10-19 | GSE105417 | GEO

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

JAK3/TEC and TYK2/JAK1 inhibitors demonstrate significant improvement in scalp alopecia areata biomarkers

Project description:We present the biopsy sub-study results from the first randomized, placebo-controlled clinical trial in patients with alopecia areata (AA) with ≥50% scalp hair loss and ≤7 years since the last AA episode. In this sub-study, we evaluated the molecular responses to PF-06651600, an oral inhibitor of JAK3 and the tyrosine kinase expressed in hepatocellular carcinoma (TEC) kinase family, and PF-06700841, an oral TYK2/JAK1 inhibitor, versus placebo in nonlesional and lesional scalp biopsies of biopsy samples from patients with AA.

2022-01-25 | GSE148346 | GEO

Transcriptomic profiling of cultured CD8+ T cells from mice and treated with either IL2, IL2/SIINFEKL(TCR), IL2/IL4, or IL2/IL4/SIINFEKL(TCR)

Project description:Transcriptomic profiling of cultured CD8+ T cells from mice and treated with either IL2, IL2/SIINFEKL(TCR), IL2/IL4, or IL2/IL4/SIINFEKL(TCR)

| PRJNA432162 | ENA

Molecular profiling of cultured CD8+ T cells from mice and treated with either IL2, IL2/SIIKFEKL(TCR), IL2/IL4, or IL2/IL4/SIINFEKL(TCR)

Project description:Molecular profiling of cultured CD8+ T cells from mice and treated with either IL2, IL2/SIIKFEKL(TCR), IL2/IL4, or IL2/IL4/SIINFEKL(TCR)

| PRJNA429800 | ENA

Transcription profiling of human JAK1 wild-type and JAK1 mutation-positive T cell acute lymphoblastic leukemia blasts

Project description:Aberrant signal transduction contributes substantially to leukemogenesis. The Janus kinase 1 (JAK1) gene encodes a cytoplasmic tyrosine kinase that noncovalently associates with a variety of cytokine receptors and plays a nonredundant role in lymphoid cell precursor proliferation, survival, and differentiation. Somatic mutations in JAK1 occur in individuals with acute lymphoblastic leukemia (ALL). JAK1 mutations were more prevalent among adult subjects with the T cell precursor ALL, where they accounted for 18% of cases, and were associated with advanced age at diagnosis, poor response to therapy, and overall prognosis; We used microarray to compare the gene expression profile of JAK1 mutation positive or negative ALL blasts Experiment Overall Design: Thawed or freshly isolated T-ALL cells (>90% blasts) were homogenized, total RNA was extracted and hybridized on Affymetrix microarrays

2009-10-02 | E-GEOD-18239 | biostudies-arrayexpress

Whole Proteomics of 24 hr pan Pim kinase inhibitor treatment of IL2 cultured CD8 T cells

Project description:T cell antigen-receptor (TCR) and cytokine receptor engagement trigger large changes in Serine/Threonine kinase signalling networks to drive T cell activation and differentiation. The role of only few kinase signalling pathways have been studied in detail, and in this context, Pim kinases are an interesting, yet understudied, family of Serine/Threonine kinases, with reported roles in key processes including survival, proliferation, metabolism across a range of cell types. T lymphocytes predominantly express PIM1 and PIM2, which are rapidly induced by TCR, costimulation and cytokine signalling. Using single shot DDA mass spectrometry we examine the impact of 24 hours treatment with two different pan-Pim kinase inhibitors PIM447 and AZD1208 on in vitro IL2 differentiated effector cytotoxic T lymphocytes. The Jak1/3 inhibitor tofacitinib was included as a control as this also blocks production of Pim kinases downstream of IL2. We find that treatment with pan-Pim kinase inhibitors has a similar phenotype to Pim1/Pim2 double deficiency, showing a reduction in proteins that are key for effector cell function: glucose transporters SLC2A1 and SLC2A3 and key effector molecule Granzyme B and an increase in the translational repressor PDCD4.

2024-04-15 | PXD051214 | Pride

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