Insulin Activates CCAAT/Enhancer Binding Proteins and Proinflammatory Gene Expression through the Phosphatidylinositol 3-Kinase Pathway in Vascular Smooth Muscle Cells

Sato, Osamu; Nishio, Yoshihiko; Egawa, Katsuya; Nakamura, Takaaki; Maegawa, Hiroshi; Kashiwagi, Atsunori

doi:10.1074/jbc.m206266200

Cited by 68 publications

(66 citation statements)

References 40 publications

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“…Thus, increased expression of Cebpb and Cebpd in aortas from hyperinsulinaemic rats may be a significant factor to induce vascular inflammation leading to atherosclerosis. Consistent with the results of a previous study [7], insulin increased levels of C/EBP-β, and C/EBP-δ in cultured VSMCs in a PI3K/Akt-dependent manner. In the hyperinsulinaemic rats, Cebpb mRNA expression in the aortas was strongly correlated with plasma insulin levels.…”

Section: Discussionsupporting

confidence: 92%

“…2a,b). As reported previously [7], two binding sites for C/EBP, located in the 5′ upstream region of Ccl2 play a crucial role in the PI3K-dependent regulation of this gene. Based on this we investigated the effects of insulin on expression of Cebpb and Cebpd and the binding of the protein products to these sites.…”

Section: Insulin Inducessupporting

confidence: 74%

“…Several clinical studies, including the UKPDS [6], have shown that insulin treatment does not increase the risk of cardiovascular disease, therefore, it may be that a decrease in insulin action in the vascular tissue is responsible for increased cardiovascular risk in the hyperinsulinaemic state. We recently reported that in the presence of physiological concentrations of insulin and continuous activation of membrane-targeted phosphatidylinositol 3-kinase (PI3K) through the overexpression of p110CAAX, Ccl2 expression is increased through the activation of transcription factors known as CCAAT/enhancer binding proteins (C/EBPs) [7]. In addition to CCL2, C/EBPs are responsible for the induction of a wide array of other genes, including those encoding proteins with a role in innate immunity, cell proliferation, adipogenesis, inflammatory response and the acute-phase response, such as IL-6, IL-8, IL-12, TNF-α and C-reactive protein (CRP) [8][9][10].…”

Section: Introductionmentioning

confidence: 99%

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Increased expression of CCAAT/enhancer binding protein-β and -δ and monocyte chemoattractant protein-1 genes in aortas from hyperinsulinaemic rats

et al. 2006

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Aims/hypothesis We evaluated whether hyperinsulinaemia stimulates the expression of transcription factor CCAAT/ enhancer binding protein (C/EBP)-β and C/EBP-δ and leads to the induction of the chemokine (C-C motif) ligand 2 gene (Ccl2, also known as MCP-1) expression in aortas. Methods Hyperinsulinaemia was induced by feeding rats a high-fructose diet. CCL2 production was analysed by ELISA. The expression of Ccl2, Cebpb and Cebpd mRNAs was investigated by quantitative RT-PCR. The binding of C/EBP-β to Ccl2 was assessed by chromatin immunoprecipitation (ChIP) assay. Results Insulin at a concentration of 10 nmol/l significantly stimulated the expression of Cebpb,Cebpd and Ccl2 mRNAs, depending on activation of phosphatidylinositol 3-kinase (PI3K) in cultured vascular smooth muscle cells. The knockdown of C/EBP-β with siRNA abolished the insulin-induced Ccl2 mRNA expression. In the aortas from fructose-fed rats, the levels of phosphorylation of Akt/protein kinase B, a downstream effector of PI3K, were also increased. The expression of Cebpb, Cebpd and Ccl2 mRNAs in the aortas from fructose-fed rats were significantly elevated, by 330, 300 and 300%, respectively, compared with those of controlfed rats. The induction Ccl2 mRNA expression in the aortas was significantly correlated with the expression of Cebpb and Cebpd mRNAs in the aortas. Furthermore, the ChIP assay showed elevated binding of C/EBP-β to the 5′ upstream region of Ccl2 in the aortas from fructose-fed rats. Conclusions/interpretation These findings clearly indicate the role of C/EBPs in the mechanism of upregulation of CCL2, an inflammation-related protein, observed in the hyperinsulinaemic state, which may initiate the process of atherosclerosis.

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Section: Discussionsupporting

confidence: 92%

Section: Insulin Inducessupporting

confidence: 74%

Section: Introductionmentioning

confidence: 99%

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Increased expression of CCAAT/enhancer binding protein-β and -δ and monocyte chemoattractant protein-1 genes in aortas from hyperinsulinaemic rats

et al. 2006

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“…This leads to enhanced specific DNA binding. Both these transcription factors are closely associated with an increase in inflammatory cytokines and chemokines in VSM cells (Sekine et al, 2002;Dwarakanath et al, 2004). Although NF-kB and C/EBP belong to the families of transcription factors, identifying the specific isoforms of each transcription factor involved in SPC-mediated MCP-1 expression is beyond the scope of this study.…”

Section: Discussionmentioning

confidence: 97%

“…Although NF-kB and C/EBP belong to the families of transcription factors, identifying the specific isoforms of each transcription factor involved in SPC-mediated MCP-1 expression is beyond the scope of this study. The MCP-1 gene promoter region contains promoter sites for both C/EBP and NF-kB (Sekine et al, 2002;Ueda et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Sphingosylphosphorylcholine is a Proinflammatory Mediator in Cerebral Arteries

Wirrig

Hunter

Mathieson

et al. 2010

J Cereb Blood Flow Metab

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Inflammation has an important function in the development of cerebral vasospasm after subarachnoid hemorrhage (SAH); however, the mediators of this inflammatory response have not been clearly identified. In this study, we have investigated the potential function of two sphingolipids, which occur naturally in plasma and serum, sphingosylphosphorylcholine (SPC) and sphingosine 1-phosphate (S1P), to act as proinflammatory mediators in cerebral artery vascular smooth muscle (VSM) cells. In rat cerebral arteries, SPC but not S1P activated p38 mitogen-activated protein kinase (MAPK). Using transcription factor arrays, two proinflammatory transcription factors activated by SPC in cerebral arteries were identified-nuclear factor-jB and CCAAT-enhancerbinding protein. Both these transcription factors were activated by SPC in a p38MAPK-dependent manner. To determine whether this contributed to vascular inflammation, an inflammatory protein array was performed, which showed that SPC increased release of the chemokine monocyte chemoattractant protein-1 (MCP-1) in cultured rat VSM cells. This increase in MCP-1 expression was confirmed in cerebral arteries. The S1P did not increase MCP-1 release. Taken together, our results suggest that SPC, but not S1P, can act as a proinflammatory mediator in cerebral arteries. This may contribute to inflammation observed after SAH and may be part of the initiating event in vasospasm.

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PTHrP‐induced MCP‐1 production by human bone marrow endothelial cells and osteoblasts promotes osteoclast differentiation and prostate cancer cell proliferation and invasion in vitro

Lü

Xiao

Galson

et al. 2007

Intl Journal of Cancer

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Prostate cancer (PCa) preferentially metastasizes to bone resulting in osteoblastic lesions with underlying osteolytic activities. The mechanisms through which PCa cells promote osteolytic activities and subsequent osteoblastic bone formation remain poorly understood. Parathyroid hormone-related protein (PTHrP), produced by bone cells and PCa, binds to receptors on osteoblasts and stimulates bone formation and resorption. We have previously reported that MCP-1 acts as a paracrine and autocrine factor for PCa progression. However, the role of PTHrP in regulating MCP-1 expression in bone microenvironment, specifically by human bone marrow endothelial cells (HBME) and osteoblasts (hFOB), as well as by PCa cells, has not been studied. Accordingly, we first determined the effect of PTHrP on MCP-1 expression by bone cells and PCa cells. PTHrP induced both MCP-1 protein and mRNA expression by HBME and hFOB cells, but not by PCa LNCaP and PC3 cells. To further determine the mechanisms of PTHrP-induced MCP-1 transcription, analysis of the MCP-1 promoter was performed. MCP-1 promoter activity was induced by PTHrP. Both C/EBPb and NF-jB binding elements are required for PTHrP-induced MCP-1 transcription. Finally, when a constitutively-active PTH receptor construct was transfected into HBME and hFOB cells, MCP-1 production was increased. The conditioned media collected from these cells induced osteoclast differentiation and PC3 proliferation and invasion in vitro. These inductions were partially inhibited by MCP-1 neutralizing antibody. We conclude that PTHrP-induced MCP-1 production by HBME and hFOB cells promotes osteoclast differentiation in vitro and such induction may play a critical role in PCa development in the bone microenvironment. ' 2007 Wiley-Liss, Inc.Key words: PTHrP; MCP-1; human bone marrow endothelial cell; prostate cancer; metastasis Bone is the most common site of prostate cancer (PCa) metastasis with skeletal metastases occurring in up to 90% of patients dying from PCa.1,2 Histological studies have revealed that bone metastatic lesions are a heterogeneous mixture of osteoblastic and osteolytic lesions, although they are most often radiographically characterized as predominately osteoblastic responses.3-6 Many reports have showed that osteoblastic metastases form on trabecular bone at the sites of previous osteoclastic resorption, and that such resorption may be required for subsequent osteoblastic bone formation.2,6 Thus, bone destruction appears to be an early stage in the development of PCa bone metastasis. However, the mechanisms through which PCa cells promote bone resorption and subsequent osteoblastic bone formation remain poorly understood.PCa metastasis develops in the skeleton through crosstalk between tumor cells and bone microenvironment. The bone microenvironment, which consists of the extracellular matrix, stromal cells, osteoblasts, osteoclasts, endothelial cells, adipocytes and hematopoietic cell lineages, produces multiple factors which can enhance the growth of PCa cells and promote tumo...

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Insulin Activates CCAAT/Enhancer Binding Proteins and Proinflammatory Gene Expression through the Phosphatidylinositol 3-Kinase Pathway in Vascular Smooth Muscle Cells

Cited by 68 publications

References 40 publications

Increased expression of CCAAT/enhancer binding protein-β and -δ and monocyte chemoattractant protein-1 genes in aortas from hyperinsulinaemic rats

Increased expression of CCAAT/enhancer binding protein-β and -δ and monocyte chemoattractant protein-1 genes in aortas from hyperinsulinaemic rats

Sphingosylphosphorylcholine is a Proinflammatory Mediator in Cerebral Arteries

PTHrP‐induced MCP‐1 production by human bone marrow endothelial cells and osteoblasts promotes osteoclast differentiation and prostate cancer cell proliferation and invasion in vitro

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