Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Effect of interleukin-1 and PDGF-DD on SMCs

ABSTRACT: This experiment tests the hypothesis that interleukin-1 promotes SMC phenotypic modulation to a distinct inflammatory state relative to the growth factor PDGF-DD. Cultured rat aortic smooth muscle cells were treated with IL-1b (2.5 ng/mL) or vehicle (0.1% BSA and 10 mM acetic acid) or PDGF-DD (30 ng/mL) or vehicle (0.01% BSA) for 24 hours prior to harvest (n=1).

ORGANISM(S): Rattus norvegicus

SUBMITTER: Gary Owens

PROVIDER: E-GEOD-31080 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Interleukin-1β modulates smooth muscle cell phenotype to a distinct inflammatory state relative to PDGF-DD via NF-κB-dependent mechanisms.

Alexander Matthew R MR Murgai Meera M Moehle Christopher W CW Owens Gary K GK

Physiological genomics 20120207 7

Smooth muscle cell (SMC) phenotypic modulation in atherosclerosis and in response to PDGF in vitro involves repression of differentiation marker genes and increases in SMC proliferation, migration, and matrix synthesis. However, SMCs within atherosclerotic plaques can also express a number of proinflammatory genes, and in cultured SMCs the inflammatory cytokine IL-1β represses SMC marker gene expression and induces inflammatory gene expression. Studies herein tested the hypothesis that IL-1β mod ...[more]

PMID: 22318995

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Project description:Background & Aims: Rapid induction of beta-PDGF receptor (beta-PDGFR) is a core feature of hepatic stellate cell activation, the hallmark of liver fibrogenesis. However, biological consequences of the induction are not well characterized. We aimed to determine the involvement of beta-PDGFR-mediated molecular pathway activation on hepatic stellate cells in liver injury, fibrogenesis, and carcinogenesis in vivo. Methods: Loss and constitutive activation of beta-PDGFR were assessed in mouse models with either a stellate cell-specific beta-PDGFR knockout or the expression of an autoactivating mutation respectively. Liver injury and fibrosis were induced in two mechanistically distinct models: carbontetrachloride (CCl4) treatment and ligation of the common bile duct. Hepatocarcinogenesis with underlying liver injury/fibrosis was assessed by a single dose of diethylnitrosamine (DEN) followed by repeated injections of CCl4. Genome-wide expression profiling was performed isolated stellate cells from these models to determine deregulated pathways. Results: Depletion of beta-PDGFR in hepatic stellate cells led to decreased histological liver injury, serum transaminases, collagen alpha 1(I) and alpha smooth muscle actin expression, and collagen deposition. Stellate cell proliferation was significantly reduced after acute hepatic injury in vivo. In contrast, autoactivation of beta-PDGFR in stellate cells accelerated liver fibrosis, most prominently after 6 weeks of CCl4 induced injury. There was no difference in development of DEN-induced pre-neoplastic loci according to the status of beta-PDGFR. Conclusions: Depletion of beta-PDGFR in hepatic stellate cells attenuated the development of liver injury, fibrosis, and stellate cell proliferation in multiple animal models, whereas the constitutive activation of beta-PDGFR enhanced fibrosis. However, manipulation of beta-PDGFR alone did not reduce development of dysplastic nodules. These findings indicate that titration of receptor beta-PDGFR expression on stellate cells parallels fibrosis and injury, but may not impact the development of hepatic neoplasia alone. Hepatic stellate cells were isolated from liver of beta-PDGFR-wild-type or knockout mice, and treated with beta-PDGF ligand or vehicle control.

Project description:Here, we report the first complete genomes of three cultivable treponeme species from bovine digital dermatitis (DD) skin lesions, two comparative human treponemes and a bovine gastrointestinal (GI) isolate. Key genomic differences between bovine and human treponemes implicate microbial mechanisms that enhance knowledge of how DD, a severe disease of ruminants, has emerged into a prolific and endemic disease in countries worldwide. Bovine DD treponemes have additional oxidative stress genes compared to nearest human-isolated relatives, suggesting better toleration of oxidative stress, and thus potentially explaining the ability of bovine strains to colonize skin surfaces. Comparison of bovine DD and GI treponemes as well as bovine pathogenic and human non-pathogenic saprophyte Treponema phagedenis strains indicates genes encoding a five-enzyme biosynthetic pathway for the production of 2,3-diacetamido-2,3-dideoxy-d-mannuronic acid, a rare di-N-acetylated mannuronic acid sugar with potential immunomodulatory activity, as important for pathogenesis. The bovine T. phagedenis strains further differed from human strains by having a larger number of unique genetic features including components of a type IV secretion system and a phosphate utilisation system including phoU, a gene associated with enhanced osmotic stress survival. Proteomic analyses confirmed bovine derived T. phagedenis exhibits expression of PhoU but not the putative secretion system whilst the novel mannuronic acid pathway was expressed in near entirety across the DD treponemes. Analysis of osmotic stress response in water identified a difference between bovine and human T. phagedenis with bovine strains surviving better. This novel mechanism could enable a selective advantage, allowing environmental persistence and transmission of bovine T. phagedenis. Finally, we investigated a range of treponeme genes encoding ortholog families across the DD treponemes representing putative outer membrane proteins (OMPs) and identified several families as multi-specific adhesins capable of binding extra cellular matrix (ECM) components. Human saprophytic T. phagedenis could not be differentiated from bovine pathogenic strains by these adhesins and only two of ten characterised ortholog OMP families were absent from commensal bovine treponemes. One of these bovine pathogen specific adhesin ortholog families showed considerable diagnostic potential with the Treponema medium representative demonstrating the greatest disease specificity (91.6%). This work has shed light on treponeme host adaptation and has identified candidate molecules for future diagnostics, vaccination and therapeutic intervention.

Dataset Information

Effect of interleukin-1 and PDGF-DD on SMCs

Publications

Interleukin-1β modulates smooth muscle cell phenotype to a distinct inflammatory state relative to PDGF-DD via NF-κB-dependent mechanisms.

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