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STAT1-dependent signal integration between IFNγ and TLR4 in vascular cells reflect pro-atherogenic responses in human atherosclerosis.

Chmielewski S, Olejnik A, Sikorski K, Pelisek J, Błaszczyk K, Aoqui C, Nowicka H, Zernecke A, Heemann U, Wesoly J, Baumann M, Bluyssen HA - PLoS ONE (2014)

Bottom Line: The synergistic interactions between IFNγ and TLR4 also resulted in increased T-cell migration and impaired aortic contractility in a STAT1-dependent manner.Expression of the chemokines CXCL9 and CXCL10 correlated with STAT1 phosphorylation in vascular cells in plaques from human carotid arteries.Moreover, using data mining of human plaque transcriptomes, expression of a selection of these STAT1-dependent pro-atherogenic genes was found to be increased in coronary artery disease (CAD) and carotid atherosclerosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Nephrology, Klinikum rechts der Isar, Technical University Munich, Munich, Germany; Department of Human Molecular Genetics, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University Poznan, Poznan, Poland.

ABSTRACT
Signal integration between IFNγ and TLRs in immune cells has been associated with the host defense against pathogens and injury, with a predominant role of STAT1. We hypothesize that STAT1-dependent transcriptional changes in vascular cells involved in cross-talk between IFNγ and TLR4, reflect pro-atherogenic responses in human atherosclerosis. Genome-wide investigation identified a set of STAT1-dependent genes that were synergistically affected by interactions between IFNγ and TLR4 in VSMCs. These included the chemokines Cxcl9, Ccl12, Ccl8, Ccrl2, Cxcl10 and Ccl5, adhesion molecules Cd40, Cd74, and antiviral and antibacterial genes Rsad2, Mx1, Oasl1, Gbp5, Nos2, Batf2 and Tnfrsf11a. Among the amplified genes was also Irf8, of which Ccl5 was subsequently identified as a new pro-inflammatory target in VSMCs and ECs. Promoter analysis predicted transcriptional cooperation between STAT1, IRF1, IRF8 and NFκB, with the novel role of IRF8 providing an additional layer to the overall complexity. The synergistic interactions between IFNγ and TLR4 also resulted in increased T-cell migration and impaired aortic contractility in a STAT1-dependent manner. Expression of the chemokines CXCL9 and CXCL10 correlated with STAT1 phosphorylation in vascular cells in plaques from human carotid arteries. Moreover, using data mining of human plaque transcriptomes, expression of a selection of these STAT1-dependent pro-atherogenic genes was found to be increased in coronary artery disease (CAD) and carotid atherosclerosis. Our study provides evidence to suggest that in ECs and VSMCs STAT1 orchestrates a platform for cross-talk between IFNγ and TLR4, and identifies a STAT1-dependent gene signature that reflects a pro-atherogenic state in human atherosclerosis.

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Expression of synergistically amplified genes in atherosclerotic vessels.A, Venn diagram with analysis of microarray datasets obtained from human coronary plaques and human carotid plaques. B, Promoter analysis of the differentially expressed genes in carotid (left panel) and coronary plaques (right panel). For details see text.
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pone-0113318-g007: Expression of synergistically amplified genes in atherosclerotic vessels.A, Venn diagram with analysis of microarray datasets obtained from human coronary plaques and human carotid plaques. B, Promoter analysis of the differentially expressed genes in carotid (left panel) and coronary plaques (right panel). For details see text.

Mentions: To obtain potential evidence for STAT1-mediated target gene expression in the human atherosclerotic plaque, we performed different types of experiments. First, we analyzed two independent microarray datasets obtained from human coronary plaques and human carotid plaques. These datasets are available in GEO NCBI database (acc. no. GSE40231 and GSE21545, respectively) [26], [27]. In coronary and carotid plaques respectively we identified 1146 and 949 genes upregulated at least 1.5 times as compared to the healthy arterial tissue (Figure 7A). 201 of those genes are commonly expressed between the different plaque tissues, highly implying that there are common features between coronary and carotid plaques (Sikorski et al. [36]). Detailed promoter analysis of the differentially expressed genes in carotid and coronary plaques identified 128 (Figure 7B) and 362 (Figure 7C) genes, respectively containing GAS, ISRE or NFκB sites, either alone or in different combinations. This strongly suggests also the cooperative involvement of NFκB, STAT1 and/or IRF in the transcriptional regulation of genes in the plaque tissue.


STAT1-dependent signal integration between IFNγ and TLR4 in vascular cells reflect pro-atherogenic responses in human atherosclerosis.

Chmielewski S, Olejnik A, Sikorski K, Pelisek J, Błaszczyk K, Aoqui C, Nowicka H, Zernecke A, Heemann U, Wesoly J, Baumann M, Bluyssen HA - PLoS ONE (2014)

Expression of synergistically amplified genes in atherosclerotic vessels.A, Venn diagram with analysis of microarray datasets obtained from human coronary plaques and human carotid plaques. B, Promoter analysis of the differentially expressed genes in carotid (left panel) and coronary plaques (right panel). For details see text.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4257532&req=5

pone-0113318-g007: Expression of synergistically amplified genes in atherosclerotic vessels.A, Venn diagram with analysis of microarray datasets obtained from human coronary plaques and human carotid plaques. B, Promoter analysis of the differentially expressed genes in carotid (left panel) and coronary plaques (right panel). For details see text.
Mentions: To obtain potential evidence for STAT1-mediated target gene expression in the human atherosclerotic plaque, we performed different types of experiments. First, we analyzed two independent microarray datasets obtained from human coronary plaques and human carotid plaques. These datasets are available in GEO NCBI database (acc. no. GSE40231 and GSE21545, respectively) [26], [27]. In coronary and carotid plaques respectively we identified 1146 and 949 genes upregulated at least 1.5 times as compared to the healthy arterial tissue (Figure 7A). 201 of those genes are commonly expressed between the different plaque tissues, highly implying that there are common features between coronary and carotid plaques (Sikorski et al. [36]). Detailed promoter analysis of the differentially expressed genes in carotid and coronary plaques identified 128 (Figure 7B) and 362 (Figure 7C) genes, respectively containing GAS, ISRE or NFκB sites, either alone or in different combinations. This strongly suggests also the cooperative involvement of NFκB, STAT1 and/or IRF in the transcriptional regulation of genes in the plaque tissue.

Bottom Line: The synergistic interactions between IFNγ and TLR4 also resulted in increased T-cell migration and impaired aortic contractility in a STAT1-dependent manner.Expression of the chemokines CXCL9 and CXCL10 correlated with STAT1 phosphorylation in vascular cells in plaques from human carotid arteries.Moreover, using data mining of human plaque transcriptomes, expression of a selection of these STAT1-dependent pro-atherogenic genes was found to be increased in coronary artery disease (CAD) and carotid atherosclerosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Nephrology, Klinikum rechts der Isar, Technical University Munich, Munich, Germany; Department of Human Molecular Genetics, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University Poznan, Poznan, Poland.

ABSTRACT
Signal integration between IFNγ and TLRs in immune cells has been associated with the host defense against pathogens and injury, with a predominant role of STAT1. We hypothesize that STAT1-dependent transcriptional changes in vascular cells involved in cross-talk between IFNγ and TLR4, reflect pro-atherogenic responses in human atherosclerosis. Genome-wide investigation identified a set of STAT1-dependent genes that were synergistically affected by interactions between IFNγ and TLR4 in VSMCs. These included the chemokines Cxcl9, Ccl12, Ccl8, Ccrl2, Cxcl10 and Ccl5, adhesion molecules Cd40, Cd74, and antiviral and antibacterial genes Rsad2, Mx1, Oasl1, Gbp5, Nos2, Batf2 and Tnfrsf11a. Among the amplified genes was also Irf8, of which Ccl5 was subsequently identified as a new pro-inflammatory target in VSMCs and ECs. Promoter analysis predicted transcriptional cooperation between STAT1, IRF1, IRF8 and NFκB, with the novel role of IRF8 providing an additional layer to the overall complexity. The synergistic interactions between IFNγ and TLR4 also resulted in increased T-cell migration and impaired aortic contractility in a STAT1-dependent manner. Expression of the chemokines CXCL9 and CXCL10 correlated with STAT1 phosphorylation in vascular cells in plaques from human carotid arteries. Moreover, using data mining of human plaque transcriptomes, expression of a selection of these STAT1-dependent pro-atherogenic genes was found to be increased in coronary artery disease (CAD) and carotid atherosclerosis. Our study provides evidence to suggest that in ECs and VSMCs STAT1 orchestrates a platform for cross-talk between IFNγ and TLR4, and identifies a STAT1-dependent gene signature that reflects a pro-atherogenic state in human atherosclerosis.

Show MeSH
Related in: MedlinePlus