Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA101903 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Activation of Sez-4 cell line with IL-2, IL-15 or IL-21.
| PRJNA101899 | ENA
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
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
Project description:Activating JAK and STAT mutations were discovered in many T-cell malignancies including ALK- anaplastic large cell lymphomas (ALCL). However, such mutations often occur in a minority of patients. To investigate the clinical application of targeting Janus Kinase (JAK) for ALK- ALCL, we treated ALK- cell lines of different histologic origins with JAK inhibitors. Interestingly, most exogenous cytokine independent cell lines responded to JAK inhibition regardless of JAK mutation status. JAK inhibitor sensitivity correlated with STAT3 phosphorylation status of tumor cells. Employing retroviral shRNA knockdown, we demonstrated that these JAK inhibitor sensitive cells were dependent on both JAK1 and STAT3 for survival. JAK1 and STAT3 gain-of-function mutations were found in some but not all JAK inhibitor sensitive cells. Moreover, the mutations alone could not explain the JAK1/STAT3 dependency as wild-type JAK1 or STAT3 was sufficient to promote cell survival in the cells that had either JAK1or STAT3 mutations. To investigate whether other mechanisms were involved, we knocked down upstream receptors GP130 or IL-2Rγ. Knockdown of GP130 or IL-2Rγ induced cell death in select JAK inhibitor sensitive cells. High levels of cytokine expression including IL-6 were demonstrated in cell lines as well as in primary ALK- ALCL tumors. Finally, ruxolitinib, a JAK1/2 inhibitor, was effective in vivo in a xenograft ALK- ALCL model. Our data suggest cytokine receptor signaling was required for tumor cell survival in diverse forms of ALK- ALCL even in the presence of JAK1/STAT3 mutations. Therefore, JAK-inhibitor therapy might benefit patients with ALK- ALCL that are pSTAT3+.
2017-08-22 | GSE96048 | GEO
Project description:Granuloma annulare (GA) is a common inflammatory cutaneous disorder characterized by macrophage accumulation and activation in the skin. Its pathogenesis is poorly understood and there are no reliably effective treatments. Its potential health implications, if any, are unknown. Using single cell RNA sequencing (scRNAseq) we show that in GA, CD4+ T cells over-produce interferon (IFN)-g resulting in inflammatory polarization of macrophages and in altered extracellular matrix (ECM) production induced by the activity of oncostatin M, an interleukin (IL)-6 family cytokine, on fibroblasts. This mechanism identifies Janus kinase (JAK) inhibition as a potential therapeutic strategy, as both IFN-g and OSM signal via the JAK-STAT pathway. Indeed, treatment of five patients with severe, longstanding GA with tofacitinib (a JAK1/3 inhibitor) resulted in clinical and histologic disease remission in three patients and marked improvement in the other two. Treatment was associated with suppression of pathogenic cytokine activity in the skin and dissolution of macrophages. We also found that severe GA was associated with hypercytokinemia in plasma of patients, and JAK inhibition normalized this hypercytokiemia. Together, our results highlight the constitutive activity of the JAK-STAT pathway in GA as a result of IFN-g and OSM and identify JAK inhibitors as a potential molecularly targeted treatment for this disorder.
2020-12-22 | GSE158923 | GEO
Project description:Granuloma annulare (GA) is a common inflammatory cutaneous disorder characterized by macrophage accumulation and activation in the skin. Its pathogenesis is poorly understood and there are no reliably effective treatments. Its potential health implications, if any, are unknown. Using single cell RNA sequencing (scRNAseq) we show that in GA, CD4+ T cells over-produce interferon (IFN)-g resulting in inflammatory polarization of macrophages and in altered extracellular matrix (ECM) production induced by the activity of oncostatin M, an interleukin (IL)-6 family cytokine, on fibroblasts. This mechanism identifies Janus kinase (JAK) inhibition as a potential therapeutic strategy, as both IFN-g and OSM signal via the JAK-STAT pathway. Indeed, treatment of five patients with severe, longstanding GA with tofacitinib (a JAK1/3 inhibitor) resulted in clinical and histologic disease remission in three patients and marked improvement in the other two. Treatment was associated with suppression of pathogenic cytokine activity in the skin and dissolution of macrophages. We also found that severe GA was associated with hypercytokinemia in plasma of patients, and JAK inhibition normalized this hypercytokiemia. Together, our results highlight the constitutive activity of the JAK-STAT pathway in GA as a result of IFN-g and OSM and identify JAK inhibitors as a potential molecularly targeted treatment for this disorder.
2020-12-22 | GSE158924 | GEO
Project description:We evaluated the efficacy of proteolysis-targeting chimeras (PROTACs) directed against Janus kinases. Solving the structure of FDA-approved type I JAK inhibitors ruxolitinib and baricitinib bound to the JAK2 JH1 tyrosine kinase domain enabled the rational design and optimization of Cereblon (CRBN)-directed JAK PROTACs utilizing multiple derivatives of JAK inhibitors, linkers and CRBN-specific molecular glues. The resulting JAK PROTACs were evaluated for target degradation by proteomic approaches, and activity tested in CRLF2-rearranged cell line and xenograft models of ALL.
| EGAS00001005180 | EGA
Project description:Isolated neutrophils were exposed to JAK inhibitors then activated with PMA to determine which pathways were dependent on JAK activation
| MSV000099341 | MassIVE
Project description:High-resolution mass spectrometry analysis of Interleukin 2 (IL-2) and Janus kinase (JAK) controlled protein phosphorylations in cytotoxic T lymphocytes (CTL) revealed JAKs coupled IL-2 receptors to diverse and complex serine/threonine kinase-substrate networks. These involved intricate, co-ordinated phosphorylation of transcription factors, chromatin regulators within the nuclear environment, cytosolic mRNA translational machinery, regulators of GTPases, vesicle trafficking proteins and the actin and microtubule cytoskeleton. We also identified an IL-2-JAK independent SRC family Tyr kinase controlled signaling network that regulates ~10% of the CTL phosphoproteome. One key signaling pathway in CTL is mediated by phosphatidylinositol (3,4,5)-trisphosphate (PIP3) and the serine/threonine kinase AKT. Strikingly, SRC family kinase dependent but JAK independent signaling controlled PIP3 levels and AKT activity in CTL. IL-2-JAK controlled signaling pathways thus coordinate with IL-2 independent networks of protein phosphorylation to program CTL fate.
2016-08-25 | PXD004645 | Pride
Project description:Targeted molecular therapy has yielded remarkable outcomes in certain cancers, but specific therapeutic targets remain elusive for many others. As a result of two independent RNA interference (RNAi) screens, we identified pathway dependence on a member of the JAK tyrosine kinase family, TYK2, and its downstream effector STAT1 in T-cell acute lymphoblastic leukemia (T-ALL). Gene knockdown experiments consistently demonstrated TYK2 dependence in both T-ALL primary specimens and cell lines, and a small-molecule inhibitor of JAK kinase activity induced T-ALL cell death. Activation of this TYK2-STAT1 pathway in T-ALL cell lines occurs by gain-of-function TYK2 mutations or activation of IL-10 receptor signaling, and this pathway mediates T-ALL cell survival through upregulation of the anti-apoptotic protein BCL2. These findings indicate that in many T-ALL cases, the leukemic cells are dependent upon the TYK2-STAT1-BCL2 pathway for continued survival, supporting the development of molecular therapies targeting TYK2 and other components of this pathway. Human T-ALL cell line JURKAT cells were transduced with TYK2 (TYK2#2 or #3), STAT1 (STAT1#2 or #3) or control shRNAs (GFP and Luc). Experiment was done in biological duplicate ("dup1" and "dup2") . A total of 12 RNA samples (4 control, 4 TYK2 knockdown and 4 STAT1 knockdown) were used for microarray gene expression analysis.
2013-03-18 | E-GEOD-44652 | biostudies-arrayexpress