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Vitamin D3 affects TNFa mediated activation of dendritic cells

ABSTRACT: The ability of dendritic cells (DC) to initiate immunity and induce antigen-specific tolerance makes DC ideal targets for pharmacological intervention into immune responses. NF-kB factors are a family of transcriptional regulators important for DC development and function. However, the identity of NF-kB target genes that are central to DC biology is largely unknown. In the present study inhibition of the NF-kB activation by the IkBa super repressor (IkBa-SR) and DNA microarray analysis were used to determine the repertoire of NF-kB responsive genes in DC. A number of immunomodulatory compounds have been suggested to target the NF-kB signalling pathway and/or NF-kB-mediated transcription of pro-inflammatory target genes. 1a,25-dihydroxyvitamin D3 (VD3) exerts its effects through the vitamin D3 receptor (VDR), a member of the nuclear hormone receptor superfamily. Microarray analysis was also selected as an approach of choice for the analysis of the effects of VD3 on the activation of DC, and to survey the involvement of VDR in repression of NF-kB regulated genes. These genes can be potentially useful targets for the development of more specific anti-inflammatory agents for clinical applications. Keywords: drug treatment, TNFa treatment, VD3 treatment

ORGANISM(S): Mus musculus

PROVIDER: GSE8334 | GEO | 2012/12/31

SECONDARY ACCESSION(S): PRJNA101331

REPOSITORIES: GEO

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Vitamin D3 affects TNFa mediated activation of dendritic cells

Project description:The ability of dendritic cells (DC) to initiate immunity and induce antigen-specific tolerance makes DC ideal targets for pharmacological intervention into immune responses. NF-kB factors are a family of transcriptional regulators important for DC development and function. However, the identity of NF-kB target genes that are central to DC biology is largely unknown. In the present study inhibition of the NF-kB activation by the IkBa super repressor (IkBa-SR) and DNA microarray analysis were used to determine the repertoire of NF-kB responsive genes in DC. A number of immunomodulatory compounds have been suggested to target the NF-kB signalling pathway and/or NF-kB-mediated transcription of pro-inflammatory target genes. 1a,25-dihydroxyvitamin D3 (VD3) exerts its effects through the vitamin D3 receptor (VDR), a member of the nuclear hormone receptor superfamily. Microarray analysis was also selected as an approach of choice for the analysis of the effects of VD3 on the activation of DC, and to survey the involvement of VDR in repression of NF-kB regulated genes. These genes can be potentially useful targets for the development of more specific anti-inflammatory agents for clinical applications. Keywords: drug treatment, TNFa treatment, VD3 treatment DC were generated in vitro from bone marrow cells of VDRmut and VDRwt control mice as described previously (Hieronymus, T., T. C. Gust, R. D. Kirsch, T. Jorgas, G. Blendinger, M. Goncharenko, K. Supplitt, S. Rose-John, A. M. Muller, and M. Zenke. 2005. Progressive and controlled development of mouse dendritic cells from Flt3+CD11b+ progenitors in vitro. J Immunol 174:2552-2562). Immature DC were pre-treated with 1a,25-dihydroxyvitamin D3 (VD3), or left untreated. TNFa was added where appropriate, and cells incubated further for 4 h. Total RNA was amplified, labelled and hybridised to Affymetrix MOE430A arrays. TNFa up- and down-regulated genes, as well as genes affected by VD3 were analysed.

2012-12-31 | E-GEOD-8334 | biostudies-arrayexpress

NF-kB target genes in dendritic cells

2012-12-31 | GSE8009 | GEO

NF-kB target genes in dendritic cells

Project description:The ability of dendritic cells (DC) to initiate immunity and induce antigen-specific tolerance makes DC ideal targets for pharmacological intervention into immune responses. NF-kB factors are a family of transcriptional regulators important for DC development and function. However, the identity of NF-kB target genes that are central to DC biology is largely unknown. In the present study IkBa super repressor (IkBa-SR) and DNA microarray analysis were used to determine the repertoire of NF-kB responsive genes in DC. In DC these genes regulate vital DC functions of antigen uptake and presentation, motility, survival, etc. Taking in account limitations of the genome-wide microarray analysis, generated transcription factor data were confirmed by the independent means of RT-PCR and chromatin immunoprecipitation. Kinetics of NF-kB induction by well-known DC activatory agents TNFa and LPS were further analysed. NF-kB regulated genes can be potentially useful targets for the development of more specific anti-inflammatory agents for clinical applications. Keywords: drug treatment, adenovirus transduction DC were generated in vitro from bone marrow of CAR transgenic mice as described previously (Hieronymus, T., T. C. Gust, R. D. Kirsch, T. Jorgas, G. Blendinger, M. Goncharenko, K. Supplitt, S. Rose-John, A. M. Muller, and M. Zenke. 2005. Progressive and controlled development of mouse dendritic cells from Flt3+CD11b+ progenitors in vitro. J Immunol 174:2552-2562). Immature DC were transduced with AdIkBa-SR adenovirus, AdOVA control virus, or left untreated. Cells were then stimulated with TNFa, or left unstimulated. Total RNA was amplified, labelled and hybridised to Affymetrix MOE430A arrays. TNFa up- and down-regulated genes, as well as genes regulated by AdOVA control virus, and suppressed by AdIkBa-SR were analysed.

2012-12-31 | E-GEOD-8009 | biostudies-arrayexpress

A novel YDDX linear motif mediates docking of the IKK kinase to substrates: structural and functional insights

Project description:The inhibitor of kB kinase (IKK) is the master regulator of the nuclear factor kB (NF-kB) pathway, involved in inflammatory, immune and apoptotic responses. In the ‘canonical’ NF-kB pathway, IKK phosphorylates inhibitor of kB (IkB) proteins and this triggers ubiquitin-mediated degradation of IkB, leading to release and nuclear translocation of NF-B transcription factors. The data presented show that the IKK and IKK subunits recognize a YDDX docking site located within the disordered C-terminal region of IkBa. Our results also suggest that IKK contributes to the docking interaction with higher affinity as compared to IKK.

2024-05-09 | PXD037534 | JPOST Repository

Mus musculus

Project description:NF-kB target genes in dendritic cells

| PRJNA100801 | ENA

Analysis of the cellular effect of 1α,25-dihydroxyvitamin D3 on lung NCI-H441 cells

Project description:Low serum levels or deficiency of 1α,25-dihydroxyvitamin D3 (VD3) are associated with a higher mortality in trauma patients with sepsis or acute respiratory distress syndrome, although the molecular mechanisms behind this observation are not yet understood. VD3 is known to stimulate lung maturity, alveolar type II cell differentiation and pulmonary surfactant synthesis. This study aims to expand the knowledge by quantitative characterization of NCI-H441 cells upon VD3 treatment at the proteome level.

2023-05-10 | PXD040622 | Pride

Polymorphisms of the vitamin D receptor regulate T cells and T cell dependent inflammatory diseases

Project description:Complex autoimmune diseases have proven difficult to dissect down to their causative genetic mechanisms. As a result, epidemiological data from different human association studies are often merged to arrive at a working hypothesis. In one of such examples, lack of sun exposure and consequent lower serum vitamin D3 levels has been proposed to increase risk of autoimmunity, attributing vitamin D3 an immune regulatory role. However, conclusive evidence demonstrating its efficacy in treating autoimmune diseases is missing. In this study, we have used a forward genetics approach to positionally identify polymorphic nucleotides controlling T cell-dependent inflammatory diseases using congenic mouse strains. Here, we identify the vitamin D3 receptor (Vdr) as a driver of inflammation. Congenic mice carrying a polymorphic Vdr allele overexpressed the receptor selectively in activated T cells, thereby escaping systemic calcaemic side effects that often constitute a confounding factor in the study of immunomodulation by vitamin D3. Mice overexpressing Vdr in T cells developed more severe collagen-induced arthritis (CIA) and exhibited an enhanced antigen-specific CD4+ T cell response. Deficiency of vitamin D3 completely protected mice from CIA by limiting the activation of antigen-specific T cell responses, and arthritis susceptibility was restored by re-administration of vitamin D3. We demonstrate that vitamin D3 signalling specifically through Vdr predominantly acts to enhance T cell proliferation, thereby contributing to inflammation. In conclusion, our results demonstrate that genetically determined expression of VDR codetermines the pro-inflammatory behaviour of activated T cells. Furthermore, our data suggest that the anti-inflammatory properties of vitamin D3 might be limited by high expression of VDR at the site of inflammation.

2020-09-28 | PXD019876 | Pride

The IKK2/NF-kB-pathway suppresses MYC-induced lymphomagenesis

Project description:Abstract. Deregulated c-MYC is found in a variety of cancers where it promotes proliferation as well as apoptosis. In many hematological malignancies enhanced NF-kB exerts prosurvival functions. Here we investigated the role of NF-kB in mouse and human c-MYC-transformed lymphomas. The NF-kB-pathway is extinguished in murine lymphoma cells and extrinsic stimuli typically inducing NF-kB activity fail to activate this pathway. Genetic activation of the NF-kB pathway induces apoptosis in these cells, while inhibition of NF-kB by an IkBa superrepressor provides a selective advantage in vivo. Furthermore, in human Burkitt´s lymphoma cells we find that NF-kB activation induces apoptosis. NF-kB upregulates Fas and predisposes to Fas-induced cell death, which is caspase 8 mediated and can be prevented by CFLAR overexpression. We conclude that c-MYC overexpression sensitizes cells to NF-kB-induced apoptosis and persistent inacvtivity of NF-kB signaling is a prerequisite for MYC-mediated tumorigenesis. We could also show that low immunogenicity and Fas insensitivity of MYC driven lymphoma cells is reversed by activation of NF-kB. Our observations provide a molecular explanation for the described absence of the NF-kB signaling in Burkitt´s lymphoma and question the applicability of NF-kB inhibitors as candidates for treatment of this cancer.

2009-07-22 | GSE17129 | GEO

Transcription profiling of human MDA-MB-231 cells infeted with Flag-SR-IkBa vs. vector

Project description:We used human Affymetrix microarrays to identify the up- or down-regulated gene expressions from MDA-MB-231 cells infected with control vector or Flag-SR-IkBa Experiment Overall Design: The pattern of gene expression from MDA-MB-231 cells transduced with retroviruses were analysed by RNA extraction and hybridization on Affymetrix microarrays. From expression profiles, we identified NF-kB target genes, and uncovered a novel and specific role of a gene in osteolytic bone metastasis.

2008-06-14 | E-GEOD-6324 | biostudies-arrayexpress

Macrophage-specific inhibition of NF-κB activation impairs foam cell survival

Project description:Macrophage death in advanced atherosclerotic lesions is a key event in the conversion of benign lesions to vulnerable plaques. One fundamental transcription factor that has been shown to play a pivotal role in cell death/survival is nuclear factor kB (NF-kB). Still, the relevance of this key transcription factor for macrophage-derived foam cell survival has not been unequivocally resolved at the molecular level. THP-1 monocytic cell lines were generated in which NF-kB activation is specifically inhibited by overexpression of a trans-dominant, non-degradable form of IkBa (IkBa (32A/36A)) under control of the macrophage-specific SR-A promoter. A diminished lipid loading during NF-κB inhibition during foam cell formation was accompanied by increased cell death. A genome-wide expression profile of NF-kB-dependent genes during foam cell formation was established showing a widespread effect on the macrophage transcriptome. The three largest functional gene clusters identified and validated by independent techniques, were those involved in lipid metabolism, apoptosis and oxidative stress. The net result of these complex gene expression changes invoked by inhibition of NF-κB activation during lipid loading is a reduction of foam cell survival through caspase-dependent apoptosis. Thus, the NF-kB-dependent gene repertoire seems essential for sustained macrophage survival during the process of pathological lipid loading. Keywords: genetic modification, lipid loading, timecourse

2009-08-11 | GSE12434 | GEO

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