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Genomic expression profiling of TNF-alpha-treated BDC2.5 diabetogenic CD4+ T cells.

ABSTRACT: TNF-alpha plays an important role in immune regulation, inflammation, and autoimmunity. Chronic TNF exposure has been shown to down-modulate T cell responses. In a mouse T cell hybridoma model, TNF attenuated T cell receptor (TCR) signaling. We have confirmed that chronic TNF and anti-TNF exposure suppressed and increased T cell responses, respectively. In adult TCR (BDC2.5) transgenic nonobese diabetic mice, DNA microarray analysis of global gene expression in BDC2.5 CD4(+) T cells in response to chronic TNF or anti-TNF exposure showed that genes involved in functional categories including T cell signaling, cell cycle, proliferation, ubiquitination, cytokine synthesis, calcium signaling, and apoptosis were modulated. Genes such as ubiquitin family genes, cytokine inducible Src homology 2-containing genes, cyclin-dependent kinase inhibitors p21, p57, calmodulin family genes (calmodulin-1, -2, and -3) and calcium channel voltage-dependent, N type alpha1B subunit (CaV2.2) were induced by TNF, whereas Vav2, Rho GTPase-activating protein, calcium channel voltage-dependent, L type alpha1C subunit (CaV1.2), IL-1 receptor-associated kinase-1 and -2, and IL enhancer binding factor 3 were reduced by TNF. Genes such as CaV1.2 and proliferating cell nuclear antigen, repressed by TNF, were induced by anti-TNF treatment. Further, we showed that chronic TNF exposure impaired NF-kappaB and adaptor protein 1 transactivation activity, leading to T cell unresponsiveness. Thus, our results present a detailed picture of transcriptional programs affected by chronic TNF exposure and provide candidate target genes that may function to mediate TNF-induced T cell unresponsiveness.

SUBMITTER: Lee LF

PROVIDER: S-EPMC2481314 | biostudies-literature | 2008 Jul

REPOSITORIES: biostudies-literature

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Genomic expression profiling of TNF-alpha-treated BDC2.5 diabetogenic CD4+ T cells.

Lee Li-Fen LF Lih Chih-Jian CJ Huang Chao-Jen CJ Cao Thai T Cohen Stanley N SN McDevitt Hugh O HO

Proceedings of the National Academy of Sciences of the United States of America 20080715 29

TNF-alpha plays an important role in immune regulation, inflammation, and autoimmunity. Chronic TNF exposure has been shown to down-modulate T cell responses. In a mouse T cell hybridoma model, TNF attenuated T cell receptor (TCR) signaling. We have confirmed that chronic TNF and anti-TNF exposure suppressed and increased T cell responses, respectively. In adult TCR (BDC2.5) transgenic nonobese diabetic mice, DNA microarray analysis of global gene expression in BDC2.5 CD4(+) T cells in response ...[more]

PMID: 18632574

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Project description:Tumor necrosis factor alpha (TNFalpha) plays an important role in immune regulation, inflammation, and autoimmunity. Chronic TNFalpha exposure has been shown to down-modulate T cell responses. In a mouse T cell hybridoma model, TNFalpha attenuated T cell receptor (TCR) signaling. We have confirmed that chronic TNFalpha and anti-TNFalpha exposure suppressed and increased T cell responses in BDC2.5 CD4+ T cells, respectively. The goal of this study is to analyze global transcriptional alterations resulting from TNFalpha treatment on TCR signaling pathways using cDNA microarrays. We found that genes involved in functional categories including T cell signaling, cell cycle, proliferation, ubiquitination, cytokine synthesis, calcium signaling, and apoptosis were modulated. Genes such as ubiquitin family genes, cytokine inducible SH2-containing genes, cyclin-dependent kinase inhibitors p21, p57, calmodulin family genes (calmodulin -V1, -V2, and ?V3) and calcium channel voltage- dependent, N type alpha1B subunit (CaV2.2) were induced by TNFalpha, while Vav2, Rho GTPase activating protein, calcium channel voltage dependent, L type alpha 1C subunit (CaV1.2), interleukin-1 (IL) receptor-associated kinase 1, and -V2 (IRAK-1and -2) and IL enhancer binding factor 3 were reduced by TNFalpha. Genes such as CaV1.2 and proliferating cell nuclear antigen, repressed by TNFalpha, were induced by anti-TNF treatment. Further, we showed that chronic TNFalpha exposure impaired NF-kappaB and AP-1 transactivation activity, leading to T cell unresponsiveness. Thus, our results present a detailed picture of transcriptional programs affected by chronic TNFalpha exposure, and provide candidate target genes, which may function to mediate TNFalpha induced T cell unresponsiveness. Set of arrays that are part of repeated experiments Keywords: Biological Replicate The experiments addressed the effect of TNF exposure. 8-12-week-old NOD.BDC2.5 transgenic mice were injected i.p. with PBS or 3 ug murine TNFalpha; on alternate days for three weeks. At day 24 of treatment, suspensions of LNs and/or splenocytes were stimulated with the indicated concentration of the mimotope (1047-7 peptide (YVAPVWVRME)) at a density of 7-8 x 106 cells/ml, in a final volume of 1 ml in 24-well plates. After prolonged in vitro culture, cells were harvested 12 hrs post transplantation. CD4+ T cells were purified by labeling of monoclonal Abs of surface markers, Vbeta4-FITC and CD4-PE and enriched by Magnetic beads selection followed by FACS sorting. The purity of CD4+ T cells ranged from 95% to 99% depending on individual CD4 T cells preparation. The data in column represents six independent repeated experiments with half of the slides being reverse replicates. We compared RNA from PBE treated group with TNF treated group without including reference RNA.

Project description:BackgroundPulpitis often are characterized as sustained inflammation and impaired pulp self-repair. Circular RNAs (circRNAs) have been reported to be involved in the development of inflammation, but their influence in pulpitis is still unidentified, which was examined in our research.MethodsIn this study, TNF-α (20 ng/mL) was used to treat DPSCs, then MTS identified cell proliferation. The circRNAs profile in DPSCs with or without TNF-α treatment was evaluated using RNA sequencing and subsequently by bioinformatics analysis. After that, the circular structure was assessed using agarose gel electrophoresis, followed by Sanger sequencing. And the circRNAs expression was ratified using quantitative real-time polymerase chain reaction in cell and tissues samples. Additionally, the plausible mechanism of circRNAs was envisaged, and the circRNA-miRNA-mRNA linkage was plotted using Cytoscape.ResultsThe treatment of TNF-α inhibited cell proliferation capabilities in DPSCs, which also made 1195 circRNA expressions undergo significant alterations. Among these changes, 11 circRNAs associated with inflammation were chosen for circular structure verification, and only seven circRNAs (hsa_circ_0001658, hsa_circ_0001978, hsa_circ_0003910, hsa_circ_0004314, hsa_circ_0004417, hsa_circ_0035915, and hsa_circ_0002545) had circular structure. Additionally, five circRNAs expressions (hsa_circ_0001978, hsa_circ_0003910, hsa_circ_0004314, hsa_circ_0004417, and hsa_circ_0035915) had significantly altered between with or without TNF-α treated DPSCs. Furthermore, hsa_circ_0001978 and hsa_circ_0004417 were increased in patients suffering from pulpitis. Furthermore, their ceRNA linkage and Kyoto Encyclopedia of Genes and Genomes analysis suggested that these two circRNAs may participate in the inflammation development of pulpitis via mitogen-activated protein kinase and the Wnt signaling pathway.ConclusionThis study revealed that the circRNAs profile was altered in TNF-α treated DPSCs. Also, hsa_circ_0001978 and hsa_circ_0004417 may be involved in the inflammation progress of pulpitis. These outcomes provided the latest information for additional research on pulpitis.

Dataset Information

Genomic expression profiling of TNF-alpha-treated BDC2.5 diabetogenic CD4+ T cells.

Publications

Genomic expression profiling of TNF-alpha-treated BDC2.5 diabetogenic CD4+ T cells.

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