Interleukin-6 Stimulates Proliferation of Cultured Vascular Smooth Muscle Cells Independently of Interleukin-1β

Morimoto, Shigeto; Nabata, T; Koh, Eio; Shiraishi, Tetsuya; Fukuo, Keisuke; Imanaka, Shunji; Kitano, Shiro; Miyashita, Yoh; Ogihara, Toshio

doi:10.1097/00005344-199117002-00026

Cited by 45 publications

(32 citation statements)

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“…The IL-6 effect on the cardiovascular system might be mediated via downstream acute-phase proteins (39) or by IL-6 per se. IL-6 stimulates endothelial activation, vascular smooth muscle cell proliferation (40), and leukocyte recruitment (41), thereby contributing to the process of atherosclerotic plaque growth (42) and instability (43). IL-6 mRNA is overexpressed in atheromatous arteries, and IL-6 expression co-localizes with macrophages in areas of plaque rupture (43).…”

Section: Discussionmentioning

confidence: 99%

Association of IL-6 and a Functional Polymorphism in the IL-6 Gene with Cardiovascular Events in Patients with CKD

Spoto

Mattace-Raso

Sijbrands

et al. 2015

Clinical Journal of the American Society of Nephrology

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Background and objectives High serum IL-6 is a major risk factor for cardiovascular disease (CVD) in the general population. This cytokine is substantially increased in patients with CKD, but it is still unknown whether the link between IL-6 and CVD in CKD is causal in nature.Design, setting, participants, & measurements In a cohort of 755 patients with stages 2-5 CKD, consecutively recruited from 22 nephrology units in southern Italy, this study assessed the relationship of serum IL-6 with history of CVD, as well as with incident cardiovascular (CV) events (mean follow up6SD, 31610 months) and used the functional polymorphism (2174 G/C) in the promoter of the IL-6 gene to investigate whether the link between IL-6 and CV events is causal.Results In adjusted analyses, serum IL-6 above the median value was associated with history of CVD (P,0.001) and predicted the incidence rate of CV events (hazard ratio, 1.66; 95% confidence interval [95% CI], 1.11 to 2.49; P=0.01). Patients homozygous for the risk allele (C) of the 2174 G/C polymorphism had higher levels of IL-6 than did those with other genotypes (P=0.04). Homozygous CC patients more frequently had a history of CVD (odds ratio, 2.15; 95% CI, 1.15 to 4.00; P=0.02) as well as a 87% higher rate of incident CV events (hazard ratio, 1.87; 95% CI, 1.02 to 3.44; P=0.04) compared with other genotypes. ConclusionsIn patients with stages 2-5 CKD, high serum IL-6 is associated with history of CVD and predicts incident CV events. The parallel relationship with history of CVD and incident CV events of the 2174 G/C polymorphism in the IL-6 gene suggests that IL-6 may be causally involved in the high CV risk in this population.

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Section: Discussionmentioning

confidence: 99%

Association of IL-6 and a Functional Polymorphism in the IL-6 Gene with Cardiovascular Events in Patients with CKD

Spoto

Mattace-Raso

Sijbrands

et al. 2015

Clinical Journal of the American Society of Nephrology

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“…*P \ 0.05, **P \ 0.01, compared with control 2 arteries at levels 10-to 40-fold higher than in non-atherosclerotic vessels and increased levels of IL-6 are associated with increased cardiovascular risk. Functional variations in the IL-6 gene may modify cardiovascular risk by affecting serum IL-6 levels and in some cases changing the structure of the IL-6 protein, which indicates that IL-6 has a role in the pathogenesis of atherosclerosis [13,14,[29][30][31]. These effects of TNF-a, MCP-1, and IL-6 connect dyslipidemia and atherosclerosis, but berberine might block this link by inhibition of TNF-a, MCP-1, and IL-6 production in macrophages to prevent the atherosclerosis.…”

Section: Discussionmentioning

confidence: 99%

Berberine inhibits the expression of TNFα, MCP-1, and IL-6 in AcLDL-stimulated macrophages through PPARγ pathway

Chen

Yang

Liu

et al. 2008

Endocr

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Macrophages are the main source of cytokines in atherosclerotic plaques. Modified low-density lipoproteins may stimulate macrophages to produce large quantities of proinflammatory cytokines that promote atherosclerosis. Berberine is the main component of the traditional Chinese medicine umbellatine, which has a widespread effect and was used to treat many diseases clinically. Our previous study found that berberine could increase adipophilin expression in macrophages, which is a target gene of PPARgamma. PPARgamma agonist could decrease proinflammatory cytokines in macrophage. In this study, we investigated the effects and the mechanism of action of berberine on the expression and secretion of TNFalpha, MCP-1, and IL-6 in vitro to identify new pharmacological actions of berberine. The results of RT-PCR and ELISA shows that berberine may inhibit the expression and secretion of the tumor necrosis factor alpha (TNFalpha), monocyte chemoattractant protein 1 (MCP-1), and interleukin-6 (IL-6) in macrophages stimulated by acetylated low-density lipoprotein (AcLDL), whereas the peroxisome proliferator-activated receptor gamma (PPARgamma) inhibitor GW9662 could attenuate this effect of berberine. This study demonstrates that berberine may inhibit the expression and production of TNF-alpha, MCP-1, and IL-6 in AcLDL-stimulated macrophages. This effect might be partially mediated through PPARgamma activity.

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“…These findings support an atherogenic role of IL-6 because genotypes precede atherosclerosis and do not change over time. The acute-phase reaction, trigged by upstream cytokines such as IL-6, likely are involved in atherosclerosis through endothelial activation, adhesion molecules release (35), vascular smooth muscle cell proliferation (36), platelet aggregability, and/or coagulation (37).…”

Section: Discussionmentioning

confidence: 99%

IL-6 Haplotypes, Inflammation, and Risk for Cardiovascular Disease in a Multiethnic Dialysis Cohort

Liu¹,

Berthier-Schaad²,

Fallin³

et al. 2006

Journal of the American Society of Nephrology

115

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It is unknown whether IL-6, a central regulator of inflammation, is a cause of or just a marker of atherosclerosis. Studies of genetic susceptibility to inflammation, however, avoid the potential for reverse causality. Variation in IL6 gene was studied as a predictor of cardiovascular disease (CVD) risk in a cohort of 775 incident dialysis patients, in whom IL-6 levels are elevated. On the basis of published resequencing data on the IL6 gene, a phylogenetic tree with three main branches (clades 1 to 3) was constructed. Two "clade tag" polymorphisms, ؊174G/C and 1888G/T, and two missense variants, Pro32Ser and Asp162Val, were genotyped. Circulating IL-6 and albumin were measured a median of 5 mo after the start of dialysis. CVD events were ascertained from medical records. During a median follow-up of 2.5 yr, 294 CVD events occurred. The two coding variants, Pro32Ser (present only in black patients, 10% Ser allele) and Asp162Val (present only in white patients, 1% Val), were associated with lower levels of IL-6 and higher levels of albumin. The common variant in the promoter region, ؊174G/C, was strongly associated with higher CVD risk and weakly with IL-6 levels. Clade 3 (؊174C carriers in the absence of 162 Val allele) was associated with higher IL-6 levels (P ‫؍‬ 0.03) and higher CVD risk (hazard ratio 1.44, P ‫؍‬ 0.006) after adjustment for covariates. The IL6 gene has functional variants that affect inflammation and risk for CVD among dialysis patients, supporting a causal role for IL6 in CVD.

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Interleukin-6 Stimulates Proliferation of Cultured Vascular Smooth Muscle Cells Independently of Interleukin-1β

Cited by 45 publications

References 0 publications

Association of IL-6 and a Functional Polymorphism in the IL-6 Gene with Cardiovascular Events in Patients with CKD

Association of IL-6 and a Functional Polymorphism in the IL-6 Gene with Cardiovascular Events in Patients with CKD

Berberine inhibits the expression of TNFα, MCP-1, and IL-6 in AcLDL-stimulated macrophages through PPARγ pathway

IL-6 Haplotypes, Inflammation, and Risk for Cardiovascular Disease in a Multiethnic Dialysis Cohort

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