Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Transcriptional responses of mouse BMM and TEPM to lipopolysaccharide (LPS)

ABSTRACT: Evolutionary change in gene expression is generally considered to be a major driver of phenotypic differences between species. We investigated innate immune diversification by analyzing inter-species differences in the transcriptional responses of primary human and mouse macrophages to the TLR4 agonist, LPS. Using a custom platform permitting cross-species interrogation coupled with deep sequencing of mRNA 5M-bM-^@M-^Y ends, we identified extensive divergence in LPS-regulated orthologous gene expression between humans and mice (24% of orthologs, http://www.macgate.qfab.org). Divergently regulated (DR) orthologs were enriched for genes encoding cellular M-bM-^@M-^\inputsM-bM-^@M-^] such as cell surface receptors (e.g. TLR6, IL-7RM-NM-1), and functional M-bM-^@M-^\outputsM-bM-^@M-^] such as inflammatory cytokines/chemokines (e.g. CCL20, CXCL13). Conversely, intracellular signaling components linking inputs to outputs were typically concordantly regulated. DR genes were associated with a large dynamic range of gene expression, and specific promoter architectural features (TATA box enrichment, CpG island depletion). Surprisingly, regulatory divergence was also associated with enhanced inter-species promoter conservation. Thus, the genes controlled by complex, highly conserved promoters that facilitate dynamic regulation are also the most susceptible to evolutionary change. Mouse macrophages (bone marrow-derived macrophages, BMM and thioglycollate-elicited peritoneal macrophages, TEPM) were stimulated with the TLR4 agonist, lipopolysaccharide, over a time course (0, 2, 6, 24h) and analysed in biological triplicate on a custom-designed, focused microarray.

ORGANISM(S): Mus musculus

SUBMITTER: Kate Schroder

PROVIDER: E-GEOD-19490 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Conservation and divergence in Toll-like receptor 4-regulated gene expression in primary human versus mouse macrophages.

Schroder Kate K Irvine Katharine M KM Taylor Martin S MS Bokil Nilesh J NJ Le Cao Kim-Anh KA Masterman Kelly-Anne KA Labzin Larisa I LI Semple Colin A CA Kapetanovic Ronan R Fairbairn Lynsey L Akalin Altuna A Faulkner Geoffrey J GJ Baillie John Kenneth JK Gongora Milena M Daub Carsten O CO Kawaji Hideya H McLachlan Geoffrey J GJ Goldman Nick N Grimmond Sean M SM Carninci Piero P Suzuki Harukazu H Hayashizaki Yoshihide Y Lenhard Boris B Hume David A DA Sweet Matthew J MJ

Proceedings of the National Academy of Sciences of the United States of America 20120326 16

Evolutionary change in gene expression is generally considered to be a major driver of phenotypic differences between species. We investigated innate immune diversification by analyzing interspecies differences in the transcriptional responses of primary human and mouse macrophages to the Toll-like receptor (TLR)-4 agonist lipopolysaccharide (LPS). By using a custom platform permitting cross-species interrogation coupled with deep sequencing of mRNA 5' ends, we identified extensive divergence in ...[more]

PMID: 22451944

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Project description:Interferon (IFN)γ and interleukin (IL)-4 are central regulators of T helper 1 (Th1) and T helper 2 (Th2) immune responses, respectively. Both cytokines have a major impact on macrophage phenotypes: IFNγ–priming and subsequent TLR4 activation induces so called classically activated macrophages that are characterized by pronounced pro-inflammatory responses, whereas IL-4–treated macrophages, commonly called alternatively activated, are known to develop enhanced capacity for endocytosis, antigen presentation, and tissue repair and are generally considered anti-inflammatory. Considering IL-4 as priming rather than activating stimulus, we now compared the TLR4–dependent global gene activation program in IFNγ– versus IL-4–pretreated mouse macrophages, which has rarely been studied so far. Although both cytokines frequently induced opposing effects on gene transcription, the subsequent activation of bone marrow-derived macrophages by lipopolysaccharide (LPS) produced a strong, priming dependent pro-inflammatory response in both macrophage types. For example, the production of key pro-inflammatory cytokines IL-6 and IL-12 was significantly higher in IL-4– versus IFNγ–primed macrophages and several cytokine genes, including Il19, Ccl17, Ccl22, Ccl24 and Cxcl5, were preferentially induced in alternatively primed and LPS activated mouse macrophages. In a subset of genes, including IL12a, IFNγ priming was actually found to suppress LPS–induced gene expression in a Stat1–dependent manner. Our data suggest that IL-4–priming is not per se anti-inflammatory but generates a macrophage that is “tissue protective” but still capable of mounting a strong inflammatory response after TLR4–dependent activation. Keywords: Gene expression profiling Gene expression was investigated in mouse bone marrow-derived macrophages (BMM). On day 7, BMM were stimulated with either IL-4 or IFNγ overnight (18h in total). LPS treatment was performed in primed and unprimed macrophages 4 h prior to harvesting. At least three independent experiments were performed for each condition.

Dataset Information

Transcriptional responses of mouse BMM and TEPM to lipopolysaccharide (LPS)

Publications

Conservation and divergence in Toll-like receptor 4-regulated gene expression in primary human versus mouse macrophages.

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