Signal transducer of inflammation gp130 modulates atherosclerosis in mice and man

Luchtefeld, Maren; Schunkert, Heribert; Stoll, Monika; Selle, Tina; Lorier, Rachel; Grote, Karsten; Sagebiel, Christian; Jagavelu, Kumaravelu; Tietge, Uwe J. F.; Assmus, Ulrike; Streetz, Konrad L.; Hengstenberg, Christian; Fischer, Marcus; Mayer, Björn; Maresso, Karen Colbert; Mokhtari, Nour Eddine El; Schreiber, Stefan; Müller, Werner; Bavendiek, Udo; Grothusen, Christina; Drexler, Helmut; Trautwein, Christian; Broeckel, Ulrich; Schieffer, Bernhard

doi:10.1084/jem.20070120

Cited by 59 publications

(48 citation statements)

References 35 publications

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“…Chronic infl ammatory diseases such as rheumathoid arthritis are typically associated with an increased CVD risk in patients ( 4,33 ), and chronic infl ammation causally contributes to atherogenesis in vivo in mouse models ( 10 ). On the other hand, plasma levels of several APPs are elevated in patients with atherosclerotic CVD and have been shown to possess a predictive value for future cardiovascular events ( 8,9 ).…”

Section: Discussionmentioning

confidence: 99%

“…For the subsequent experiment as-(APPs) have been shown to possess a predictive value for future cardiovascular events ( 8,9 ). Recently, it was also demonstrated that eliminating a large part of the hepatic acute phase response (APR) by knocking out the gp130 receptor on hepatocytes confers signifi cant protection from atherosclerosis, indicating that APP might mechanistically contribute to the atherosclerotic process ( 10 ). Furthermore, infl ammation impacts on HDL metabolism resulting in accelerated HDL catabolism and substantial remodeling of the HDL particle (11)(12)(13), making it likely that these changes might translate into altered in vivo RCT.…”

Section: In Vivo Reverse Cholesterol Transport Studiesmentioning

confidence: 99%

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Myeloperoxidase and serum amyloid A contribute to impaired in vivo reverse cholesterol transport during the acute phase response but not group IIA secretory phospholipase A2

Annema

Nijstad

Tölle

et al. 2010

Journal of Lipid Research

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118

129

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lesterol transport during the acute phase response but not group IIA secretory phospholipase A 2 . J. Lipid Res . 2010. 51: 743-754. Supplementary key words feces • infl ammation • sepsis • atherosclerosis • miceEpidemiological studies established a strong inverse association between plasma HDL cholesterol levels and the risk of atherosclerotic cardiovascular disease (CVD) ( 1, 2 ). A major anti-atherogenic activity of HDL is regarded to be reverse cholesterol transport (RCT), a process comprising removal of excess cholesterol from peripheral cells, most importantly macrophage foam cells in atherosclerotic lesions, and transport back to the liver for subsequent excretion into bile and feces ( 2, 3 ). Understanding the pathophysiological factors regulating RCT is therefore of prime importance.Infl ammation is strongly linked to atherosclerosis ( 4-6 ). The atherosclerotic plaque itself is increasingly considered a site of chronic infl ammation within the vessel wall ( 5, 7 ). In addition, markers of infl ammation are elevated in plasma of patients with established atherosclerotic CVD, and circulating levels of several acute phase proteins Abstract Atherosclerosis is linked to infl ammation. HDL protects against atherosclerotic cardiovascular disease, mainly by mediating cholesterol effl ux and reverse cholesterol transport (RCT). The present study aimed to test the impact of acute infl ammation as well as selected acute phase proteins on RCT with a macrophage-to-feces in vivo RCT assay using intraperitoneal administration of [ 3 H]cholesterol-labeled macrophage foam cells. In patients with acute sepsis, cholesterol effl ux toward plasma and HDL were signifi cantly decreased ( P < 0.001). In mice, acute infl ammation (75 µg/mouse lipopolysaccharide) decreased [ 3 H] cholesterol appearance in plasma ( P < 0.05) and tracer excretion into feces both within bile acids ( ؊ 84%) and neutral sterols ( ؊ 79%, each P < 0.001). In the absence of systemic infl ammation, overexpression of serum amyloid A (SAA, adenovirus) reduced overall RCT ( P < 0.05), whereas secretory phospholipase A 2 (sPLA 2 , transgenic mice) had no effect. Myeloperoxidase injection reduced tracer appearance in plasma ( P < 0.05) as well as RCT ( ؊ 36%, P < 0.05). Hepatic expression of bile acid synthesis genes ( P < 0.01) and transporters mediating biliary sterol excretion ( P < 0.01) was decreased by infl ammation. In conclusion, our data demonstrate that acute infl ammation impairs cholesterol effl ux in patients and macrophage-to-feces RCT in vivo in mice. Myeloperoxidase and SAA contribute to a certain extent to reduced RCT during infl ammation but not sPLA 2 . However, reduced bile acid formation and decreased biliary sterol excretion might represent major contributing factors to decreased RCT in infl ammation. -Annema, W., N. Nijstad, M. Tölle, J. F. de Boer, R. V. C. Buijs, P. Heeringa, M. van der Giet, and U. J. F. Tietge. Myeloperoxidase and serum amyloid A contribute to impaired in vivo reverse cho-

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Section: Discussionmentioning

confidence: 99%

Section: In Vivo Reverse Cholesterol Transport Studiesmentioning

confidence: 99%

Myeloperoxidase and serum amyloid A contribute to impaired in vivo reverse cholesterol transport during the acute phase response but not group IIA secretory phospholipase A2

Annema

Nijstad

Tölle

et al. 2010

Journal of Lipid Research

Self Cite

118

129

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“…38 Polymorphisms of IL-6ST significantly increase the risk of coronary artery disease and myocardial infarction in humans. 39 CNVs at Chr5:55326203 were associated with apoB concentration in NPHS-II, and this association was replicated in the NFBC1966 cohort.…”

Section: Discussionmentioning

confidence: 71%

Gene-Targeted Analysis of Copy Number Variants Identifies 3 Novel Associations With Coronary Heart Disease Traits

Costelloe

Moustafa

Drenos

et al. 2012

Circ Cardiovasc Genet

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Background— Copy number variants (CNVs) are a major form of genomic variation, which may be implicated in complex disease phenotypes. However, investigation of the role of CNVs in coronary heart disease (CHD) traits has been limited. Methods and Results— We examined the use of the cnvHap algorithm for CNV detection, using data for 2500 men from the Second Northwick Park Heart Study (NPHS-II). An Illumina custom chip, including 722 single-nucleotide polymorphisms covering 76 coronary heart disease-trait genes, was used. Common CNVs were significantly associated (at P <0.05, after correction) with coronary heart disease phenotypes in 5 genes. Novel associations of CNVs in toll-like receptor-4 with apolipoprotein AI were replicated ( P <0.05) in the Whitehall II cohort (4887 subjects), whereas newly described associations of CNVs in sterol regulatory element-binding protein with apolipoprotein AI and associations of interleukin-6 signal transducer with apolipoprotein B were replicated in the data from 3546 subjects from the North Finnish Birth Cohort 1966 ( P <0.05). Conclusions— This study supports the use of CNV detection algorithms such as cnvHap as potential tools for the identification of novel CNVs, some of which show significant association and replication with coronary heart disease risk phenotypes. However, the functional basis for these associations requires further substantiation.

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“…The subsequent dimerization of two gp130 proteins activates the intracellular pathways, resulting in the induction of the acute phase response [8,9]. Soluble forms of IL-6R (sIL-6R) also trigger gp130 dimerization and signalling when complexed with IL-6 [10].…”

Section: Introductionmentioning

confidence: 99%

An inhibitor of interleukin-6 trans-signalling, sgp130, contributes to impaired acute phase response in human chronic liver disease

Lemmers

Gustot

Durnez

et al. 2009

Clinical and Experimental Immunology

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SummaryIn chronic liver disease, high circulating interleukin (IL)-6 contrasts with a poor acute phase response. We evaluated the impact of liver and circulating IL-6-receptor (IL-6R) forms on IL-6 bioactivity in chronic liver disease. IL-6, soluble IL-6-receptor and sgp130 levels were assayed in plasma from 45 patients with alcoholic liver disease, 84 with hepatitis C virus (HCV) infection undergoing transjugular liver biopsies and 15 healthy subjects. IL-6R mRNA was quantified on liver extracts from 54 patients with alcoholic liver disease with or without cirrhosis and 18 HCV-infected patients. The effect of gp130-Fc on fibrinogen secretion induced by IL-6 trans-signalling was evaluated on hepatocyte cultures. Levels of plasma IL-6 and sgp130, but not soluble IL-6R, increased with the stage of chronic liver disease, and correlated significantly with disease severity. Alcoholic liver disease patients had higher plasma IL-6 levels than hepatitis C, but lower liver IL-6R expression. In alcoholic and HCV-related liver diseases, liver IL-6R expression decreased with advanced fibrosis stage. In vitro, on hepatocytes, gp130-Fc blunted the acute phase response while soluble IL-6R enhanced IL-6 stimulation. In advanced chronic liver disease, high plasma IL-6 is associated with low liver IL-6R expression. This situation enables high plasma sgp130 to act as a major negative regulator of liver IL-6 trans-signalling, as demonstrated functionally here on hepatocytes. This might explain the poor acute phase response induced by IL-6 in chronic liver disease.

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Signal transducer of inflammation gp130 modulates atherosclerosis in mice and man

Cited by 59 publications

References 35 publications

Myeloperoxidase and serum amyloid A contribute to impaired in vivo reverse cholesterol transport during the acute phase response but not group IIA secretory phospholipase A2

Myeloperoxidase and serum amyloid A contribute to impaired in vivo reverse cholesterol transport during the acute phase response but not group IIA secretory phospholipase A2

Gene-Targeted Analysis of Copy Number Variants Identifies 3 Novel Associations With Coronary Heart Disease Traits

An inhibitor of interleukin-6 trans-signalling, sgp130, contributes to impaired acute phase response in human chronic liver disease

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