Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA107765 | ENA |
REPOSITORIES: ENA
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Project description:The CD40-CD40L dyad seems to play a prominent role fostering the immune-inflammatory response triggered by endothelial cell (EC)-T cell interaction. To comprehensively delineate the involvement of CD40 (TNFRSF5) in EC activation, we combined RNAi-mediated CD40 knock-down with comparative genome-wide transcriptional profiling of EC in response to T cell. We report the initiation of a profound stress response in ECs upon CD40-CD40L engagement through early up-regulation, among others, of the major pro-inflammatory NFkB and MAPK/SAPK pathways and their associated transcription factors. Moreover, we have identified novel genes regulated through the CD40-CD40L interaction, and pathways previously unrecognized to be induced by CD40 signaling in ECs. Thus, we document a strong down-regulation of endothelial APLN by CD40-CD40L interaction, which could lead to vascular tone dysfunction in atherosclerotic lesions. Conversely, CD40-mediated up-regulation of the viral immune surveillance system, notably TLR3, IFIH1, RIG-I, and RNASEL, establishes a reverse link from adaptive to innate immunity in ECs. Moreover, systematic enrichment analysis substantiates endothelial CD40 involvement in the transcriptional regulation of gene networks associated with adhesion and motility, immunity, cell fate control, hemostasis and metabolism. Our study also highlights the potency and specificity of CD40 siRNA mediated inhibition, and the relevance of CD40 signaling pathways for anti-inflammatory therapeutic intervention. Experiment Overall Design: Time course experiment comparing endothelial gene expression profiling of CD40-silenced versus non-silenced cultured cells using RNA interference. Two independent experiments were performed where HUVECs were siRNA-transfected and co-cultured with Jurkat D1.1 for 4, 10, 16 h and harvested for RNA extraction. Technical dye swap duplicates were performed for each of the two biological replicates in all three time points.
2009-02-21 | E-GEOD-10601 | biostudies-arrayexpress
Project description:The CD40-CD40L dyad seems to play a prominent role fostering the immune-inflammatory response triggered by endothelial cell (EC)-T cell interaction. To comprehensively delineate the involvement of CD40 (TNFRSF5) in EC activation, we combined RNAi-mediated CD40 knock-down with comparative genome-wide transcriptional profiling of EC in response to T cell. We report the initiation of a profound stress response in ECs upon CD40-CD40L engagement through early up-regulation, among others, of the major pro-inflammatory NFkB and MAPK/SAPK pathways and their associated transcription factors. Moreover, we have identified novel genes regulated through the CD40-CD40L interaction, and pathways previously unrecognized to be induced by CD40 signaling in ECs. Thus, we document a strong down-regulation of endothelial APLN by CD40-CD40L interaction, which could lead to vascular tone dysfunction in atherosclerotic lesions. Conversely, CD40-mediated up-regulation of the viral immune surveillance system, notably TLR3, IFIH1, RIG-I, and RNASEL, establishes a reverse link from adaptive to innate immunity in ECs. Moreover, systematic enrichment analysis substantiates endothelial CD40 involvement in the transcriptional regulation of gene networks associated with adhesion and motility, immunity, cell fate control, hemostasis and metabolism. Our study also highlights the potency and specificity of CD40 siRNA mediated inhibition, and the relevance of CD40 signaling pathways for anti-inflammatory therapeutic intervention. Keywords: treated vs. untreated comparison, time course
2009-02-10 | GSE10601 | GEO
Project description:Gene Expression dynamics is important information. To know IKK- or ERK-dependent B cell receptor- or CD40-induced gene expression dynamics, we performed the time course and dose response analysis in wild type or MEK inhibitor treated or IKKbeta inactive DT40 B cells. Two replicated samples were analysed. Unstimulated cells (T0) were control. WT cells or MEK Inh. (MEK inhibitor;U0126 5mM, 30min pretreated) or IKKbetaSA (S176/181A knock-in) Cells were stimulated with 0.1, 1, 10 µg/ml of anti-IgM (M4) or 1, 3, 6 µg/ml of CD40ligand (CD40L) for 0, 15, 30, 45, 60 or 90min.
2014-08-01 | E-GEOD-59002 | biostudies-arrayexpress
Project description:Expression of CD40 in non-hematopoietic cells has been linked to inflammation. We presented evidence that CD40, a T-cell costimulatory molecule, is expressed in human β-cells and the engagement of CD40 in insulinoma cells activated the NFKB and ERK1/2 pathways. CD40 activation in human islets cells induced secretion of IL-8, MCP-1 and MIP-1 β, which is abrogated by inhibitors of NFkB and ERK1/2 inhibitors. In this study, we have studied gene expression mediated by CD40-CD40L interaction in islet cells. This approach identified 90 genes and transcripts exhibiting at least a 1.7 fold increase in their expression intensity after treatment with soluble CD40L. A significant number of genes were related to inflammation and oxidative stress. We have a strong overexpression of CXCL1 (Groα), CXCL2 (Mif2) and CXCL3; chemokines belonging to CXC family structurally related to Il-8. 11 genes were selected from this group and further quantified by Real Time PCR, including CXCL1. Activation of islet cells with CD40L induced the secretion of CXCL1 in a NFKB dependent manner. Engagement of CD40 in islet cells did not induce apoptosis, neither β-cell death and did not enhanced TNF-α mediated cell death as observed in insulinoma cells. CD40 activation in insulinoma cells, results in ERK1/2 dependent phsophorylation of synapsin I, a protein associated with the exocytosis machinery in neurons and β-cells. However, treatment of islets with soluble CD40L did not affect glucose induced insulin secretion. It has been reported that ductal cells always present in human islet preparations express CD40 constitutively (ref). We found that CD40-CD40L interaction in ductal cells, unlike in β-cells, induces secretion of diabetogenic cytokines IFNγ and TNF-α. Furthermore, incubation of islets containing ductal cells with CD40L decreased β-cells viability as assessed by measurement of their mitochondrial membrane potential Experiment Overall Design: We isolated islet cells from three patients. Part of islet cells from each patient has been treated with CD40L. We compared gene expression in treated cells vs untreated for each patient using dye-swap.
2008-10-20 | E-GEOD-8873 | biostudies-arrayexpress
Project description:Expression of CD40 in non-hematopoietic cells has been linked to inflammation. We presented evidence that CD40, a T-cell costimulatory molecule, is expressed in human β-cells and the engagement of CD40 in insulinoma cells activated the NFKB and ERK1/2 pathways. CD40 activation in human islets cells induced secretion of IL-8, MCP-1 and MIP-1 β, which is abrogated by inhibitors of NFkB and ERK1/2 inhibitors. In this study, we have studied gene expression mediated by CD40-CD40L interaction in islet cells. This approach identified 90 genes and transcripts exhibiting at least a 1.7 fold increase in their expression intensity after treatment with soluble CD40L. A significant number of genes were related to inflammation and oxidative stress. We have a strong overexpression of CXCL1 (Groα), CXCL2 (Mif2) and CXCL3; chemokines belonging to CXC family structurally related to Il-8. 11 genes were selected from this group and further quantified by Real Time PCR, including CXCL1. Activation of islet cells with CD40L induced the secretion of CXCL1 in a NFKB dependent manner. Engagement of CD40 in islet cells did not induce apoptosis, neither β-cell death and did not enhanced TNF-α mediated cell death as observed in insulinoma cells. CD40 activation in insulinoma cells, results in ERK1/2 dependent phsophorylation of synapsin I, a protein associated with the exocytosis machinery in neurons and β-cells. However, treatment of islets with soluble CD40L did not affect glucose induced insulin secretion. It has been reported that ductal cells always present in human islet preparations express CD40 constitutively (ref). We found that CD40-CD40L interaction in ductal cells, unlike in β-cells, induces secretion of diabetogenic cytokines IFNγ and TNF-α. Furthermore, incubation of islets containing ductal cells with CD40L decreased β-cells viability as assessed by measurement of their mitochondrial membrane potential Keywords: Pancreas, Islets of Langerhans, chemokines, cytokines, inflammation, apoptosis, Nuclear Factor-κB(NFκB)
2008-08-01 | GSE8873 | GEO
Project description:We examined the major patterns of changes in gene expression in mouse splenic B cells in response to stimulation with 33 single ligands for 0.5, 1, 2, and 4 h. We found that ligands known to directly induce or costimulate proliferation, namely, anti-IgM (anti-Ig), anti-CD40 (CD40L), LPS, and, to a lesser extent, IL-4 and CpG-oligodeoxynucleotide (CpG), induced significant expression changes in a large number of genes. The remaining 28 single ligands produced changes in relatively few genes, even though they elicited measurable elevations in intracellular Ca2+ and cAMP concentration and/or protein phosphorylation, including cytokines, chemokines, and other ligands that interact with G protein-coupled receptors. A detailed comparison of gene expression responses to anti-Ig, CD40L, LPS, IL-4, and CpG indicates that while many genes had similar temporal patterns of change in expression in response to these ligands, subsets of genes showed unique expression patterns in response to IL-4, anti-Ig, and CD40L.
2004-12-08 | E-GEOD-2050 | biostudies-arrayexpress
Project description:Pro-inflammation triggered by microbial lipopolysaccharide (LPS) through Toll-like receptor (TLR) 4 in the presence of interferon (IFN)-g induces cytokine secretion in dendritic cells (DCs) tightly regulated by a defined differentiation program. This DC differentiation is characterized by a dynamic immune activating but also tolerance inducing phenotype associated with irreversible down-modulation of cytokines. CD40L on activated T cells further modifies DC differentiation. Using DNA micro arrays we showed down-regulated mRNA levels of TLR signaling molecules while CD40/CD40L signaling molecules were up-regulated at a time when LPS/IFN-g activated DCs have ceased cytokine expression. Accordingly we demonstrated that CD40/CD40L but not TLR4 or TLR3 signaling mediated by LPS or poly (cytidylic-inosinic) acid (poly I:C) and dsRNA re-established the capacity to secret interleukin (IL)-12 in LPS/IFN-g activated DCs, which have exhausted their potential for cytokine secretion. This resulting TH1 polarizing DC phenotype – which lacked accompanying secretion of the crucial immune suppressive IL-10 - enhanced activation of cytotoxic T lymphocytes (CTLs). We therefore conclude that immune modulation is restricted to a secondary T-cell mediated stimulus at an exhausted DC state which prevents an immune tolerant DC phenotype. These findings impacts on the rational design of TLR activated DC-based cancer vaccines for the induction of anti-tumoral CTL responses. Keywords: time course
2009-04-22 | GSE11327 | GEO
Project description:Atherosclerosis, the underlying vascular cause of cardiovascular disease, has a strong inflammatory component. The co-stimulatory CD40-CD40 ligand (CD40L) signaling axis is a pivotal regulator of immune responses in atherosclerosis. However, therapeutic long-term inhibition of CD40L will severely compromise the immune system making it a non-viable treatment option. To circumvent this issue, cell-specific inhibition may present a better approach to target the CD40-CD40L axis. Therefore, we generated T cell and platelet-specific knockout mice for CD40L and apolipoprotein E, which were aged for 28 weeks to study their effects on immune status and atherosclerosis. Here, we show that T cell specific deficiency in CD40L signaling reduced plaque progression through hampered Th1 polarization as well as reduced antigen-dependent proliferation and oxLDL IgM production. DC-specific CD40 deficient mice displayed a similar phenotype. Platelet-specific CD40L deficiency, however, failed to decrease atherosclerosis, but ameliorated atherothrombosis. Together, our results illuminate the divergent cell-specific mechanisms of CD40-CD40L signaling in atherosclerosis, which may lead to advances in targeted therapies.
2021-03-16 | GSE145585 | GEO
Project description:The interaction between the transmembrane glycoprotein surface receptor CD40 expressed by skin keratinocytes (KCs) and its T cell-expressed ligand CD154 was suggested to exacerbate inflammatory skin diseases. However, the full spectrum of CD40-mediated effects by KCs underlying this observation is unknown. Therefore, changes in gene expression after CD40 ligation of KCs were studied by microarrays. CD40-mediated activation for 2 hours stimulated the expression of a coordinated network of immune-involved genes strongly interconnected by IL8 and TNF, while after 24 hours anti-proliferative and anti-apoptotic genes were upregulated. CD40 ligation stimulated the production of chemokines that attracted lymphocytes and myeloid cells from peripheral blood mononuclear cells (PBMCs). Thus, CD40-mediated activation of KCs resulted in a highly coordinated response of genes required for the local development and sustainment of adaptive immune responses. The importance of this process was confirmed by a study on the effects of human papilloma virus (HPV) infection to the KCâs response to CD40 ligation. HPV infection clearly attenuated the magnitude of the response to CD40 ligation and consequently the KCâs capacity to attract PBMCs. The fact that HPV attenuates CD40 signalling in KCs indicates the importance of the CD40-CD154 immune pathway in boosting cellular immunity within epithelia. Total RNA from eight 72 hours 50 IU/ml IFNgamma pre-stimulated primary undifferentiated keratinocyte cultures, four uninfected and four HPV-positive, that were either left unstimulated, or stimulated for 2 hours with IFNgamma and Control- or CD40L-expressing L-cells (mouse fibroblasts), or stimulated for 24 hours with IFNgamma and Control- or CD40L-expressing L-cells. The stimulated samples were generated in duplo. 72 samples were generated in total.
2015-10-26 | E-GEOD-54181 | biostudies-arrayexpress
Project description:Gene Expression dynamics is important information. To know IKK- or ERK-dependent B cell receptor- or CD40-induced gene expression dynamics, we performed the time course and dose response analysis in wild type or MEK inhibitor treated or IKKbeta inactive DT40 B cells.
2014-08-01 | GSE59002 | GEO