Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Transcription profiling of mouse bone marrow-derived macrophages simulated with LPS, time series

ABSTRACT: The innate immune system is a two-edged sword; it is absolutely required for host defense against infection, but if left uncontrolled can trigger a plethora of inflammatory diseases. Here we used systems biology approaches to predict and validate a gene regulatory network involving a dynamic interplay between the transcription factors NF-ÎºB, C/EBPÎ´, and ATF3 that controls inflammatory responses. We mathematically modeled transcriptional regulation of Il6 and Cebpd genes and experimentally validated the prediction that the combination of an initiator (NF-ÎºB), an amplifier (C/EBPÎ´) and an attenuator (ATF3) forms a regulatory circuit that discriminates between transient and persistent Toll-like receptor 4-induced signals. Our results suggest a mechanism that enables the innate immune system to detect the duration of infection and to respond appropriately. Experiment Overall Design: Bone marrow-derived macrophages stimulated with LPS for 0, 20, 40, 60, 80, 120, 240 and 360 minutes.

ORGANISM(S): Mus musculus

SUBMITTER: Bruz Marzolf

PROVIDER: E-GEOD-14769 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Function of C/EBPdelta in a regulatory circuit that discriminates between transient and persistent TLR4-induced signals.

Litvak Vladimir V Ramsey Stephen A SA Rust Alistair G AG Zak Daniel E DE Kennedy Kathleen A KA Lampano Aaron E AE Nykter Matti M Shmulevich Ilya I Aderem Alan A

Nature immunology 20090308 4

The innate immune system is like a double-edged sword: it is absolutely required for host defense against infection, but when uncontrolled, it can trigger a plethora of inflammatory diseases. Here we use systems-biology approaches to predict and confirm the existence of a gene-regulatory network involving dynamic interaction among the transcription factors NF-kappaB, C/EBPdelta and ATF3 that controls inflammatory responses. We mathematically modeled transcriptional regulation of the genes encodi ...[more]

PMID: 19270711

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Project description:MALT lymphoma is characterized by t(11;18)(q21;q21)/API2-MALT1, t(1;14)(p22;q32)/BCL10-IGH and t(14;18)(q32;q21)/IGH-MALT1, which commonly activate the NF-ÎºB pathway. Gastric MALT lymphomas harboring such translocation do not respond to H. pylori eradication, while those without translocation can be cured by antibiotics. To understand the molecular mechanism of these different MALT lymphoma subgroups, we performed gene expression profiling analysis of 24 MALT lymphomas (15 translocation-positive, 9 translocation-negative). Gene set enrichment analysis (GSEA) of the NF-ÎºB target genes and 4394 additional gene sets covering various cellular pathways, biological processes and molecular functions showed that translocation-positive MALT lymphomas are characterized by an enhanced expression of NF-ÎºB target genes, particularly TLR6, CCR2, CD69 and BCL2, while translocation-negative cases were featured by active inflammatory and immune responses, such as IL8, CD86, CD28 and ICOS. Separate analyses of the genes differentially expressed between translocation-positive and negative cases and measurement of gene ontology term in these differentially expressed genes by hypergeometric test reinforced the above findings by GSEA. Finally, expression of TLR6, in the presence of TLR2, enhanced both API2-MALT1 and BCL10 mediated NF-ÎºB activation in vitro. Our findings provide novel insights into the molecular mechanism of MALT lymphomas with and without translocation, potentially explaining their different clinical behaviors. This study compares MALT with other lymphomas, namely follicular lymphomas (FL) and mantle cell lymphomas (MCL), and investigates the molecular mechanisms of the lymphomagenesis between translocation-positive versus -negative MALT lymphoma cases in order to derive the pathways leading to MALT lymphoma pathogenesis. The study uses fresh frozen tissues from 24 MALT lymphoma cases with 7 FL and 7 MCL. Samples were run on the HG-U133A, HG-U133B, and HG-U133 plus2 GeneChips.

Project description:Mouse aorta smooth muscle cells (SMCs) express TNF receptor superfamily member 1A (TNFR1) and lymphotoxin Ã receptor (LTÃR). Circumstantial evidence has linked the SMC LTÃR to tertiary lymphoid organogenesis in diseased aortae of hyperlipidemic mice. Here, we explored potential roles of TNFR1 and LTÃR activation in cultured SMCs. TNFR1 signaling by TNF activated the classical RelA NF-ÎºB pathway, whereas LTÃR signaling by agonistic anti LTÃR antibody activated both the classical RelA and alternative RelB NF-ÎºB pathways. Addition of both agonists synergized to enhance p100 inhibitor processing to the p52 subunit of NF-ÎºB and promoted its nuclear translocation suggesting RelA-RelB cross-talk in transcription regulation. Correspondingly, microarrays showed that simultaneous TNFR1 and LTÃR activation when compared to activation of single receptors was followed by markedly elevated levels of mRNAs encoding leukocyte homeostatic chemokines CCL2, CCL5, CXCL1, and CX3CL1. Furthermore, SMCs acquired prototypical features of mesenchymal cells known as lymphoid tissue organizers (LTOs), which control tertiary lymphoid organogenesis in autoimmune diseases, through hyperinduction of CCL7, CCL9, CXCL13, CCL19, CXCL16, VCAM-1, and ICAM-1. Experiments with ltbr-/- SMCs suggested that the LTÃR-RelB activation component of NF-ÎºB signaling was obligatory to generate the LTO phenotype. TNFR1-LTÃR crosstalk also resulted in augmented synthesis and prolonged secretion of lymphorganogenic chemokine proteins into the culture medium. Thus, combined TNFR1-LTÃR signaling triggers SMC transdifferentiation into a phenotype that strikingly resembles LTOs. LTO-like SMCs may adopt a thus far unrecognized role in diseased arteries, i.e. to coordinate tertiary lymphoid organogenesis in atherosclerosis, aortic aneurysm, and transplant vasculopathy. Experiment Overall Design: Smooth muscle cells in tissue culture were stimulated with agonists and subsequently microarray, RT-PCR, and protein assays / analyses were performed

Dataset Information

Transcription profiling of mouse bone marrow-derived macrophages simulated with LPS, time series

Publications

Function of C/EBPdelta in a regulatory circuit that discriminates between transient and persistent TLR4-induced signals.

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