Lysophosphatidylcholine Induces Early Growth Response Factor-1 Expression and Activates the Core Promoter of PDGF-A Chain in Vascular Endothelial Cells

Morimoto, Masafumi; Kume, Noriaki; Miyamoto, Susumu; Ueno, Yasushi; Kataoka, Hiroharu; Minami, Manabu; Hayashida, Kazutaka; Hashimoto, Nobuo; Kita, Toru

doi:10.1161/01.atv.21.5.771

Cited by 24 publications

(14 citation statements)

References 64 publications

(57 reference statements)

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“…Several studies have shown that ERK regulates Egr-1-mediated PDGF-A and PDGF-C expression (19,32,33). We found that inhibition of the ERK signaling pathway with the MEK inhibitor PD98059 did not reduce IL-13-stimulated Egr-1 production but instead increased Stat6 phosphorylation and resulted in increased Egr-1 protein expression (Fig.…”

Section: Discussionmentioning

confidence: 68%

Opposing Actions of Stat1 and Stat6 on IL-13-Induced Up-Regulation of Early Growth Response-1 and Platelet-Derived Growth Factor Ligands in Pulmonary Fibroblasts

Ingram

Antao-Menezes

Mangum

et al. 2006

The Journal of Immunology

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IL-13 is a key cytokine involved in airway remodeling in asthma. We previously reported that IL-13 stimulated the mitogenesis of lung fibroblasts via platelet-derived growth factor (PDGF)-AA. In this report, we show that IL-13 increases PDGF-A and PDGF-C mRNA levels through a dual intracellular cascade that requires coactivation of Stat6 and Stat1 to impact transcriptional regulation of the early growth response (Egr)-1 gene, which then drives PDGF expression. Increased levels of PDGF-AA and PDGF-CC protein were observed in vivo in the airways of IL-13 transgenic mice. IL-13 up-regulated PDGF-A and PDGF-C mRNA levels in lung fibroblasts isolated from three different background strains of mice. However, IL-13-induced PDGF-A and PDGF-C mRNA levels were significantly reduced in Stat6-deficient (Stat6−/−) fibroblasts as compared with wild-type Stat6+/+ fibroblasts. In contrast, IL-13-induced PDGF-A and PDGF-C mRNAs were enhanced in Stat1−/− fibroblasts as compared with Stat1+/+ fibroblasts. IL-13 did not up-regulate PDGF-A or PDGF-C mRNA levels in Egr-1−/− fibroblasts. Moreover, IL-13 did not increase Egr-1 mRNA and protein levels in Stat6−/− fibroblasts and yet enhanced Egr-1 mRNA and protein levels in Stat1−/− fibroblasts. Our findings support the hypothesis that Stat6 and Stat1 exert stimulatory and inhibitory effects on Egr-1 and PDGF ligand mRNA transcription, respectively. This novel mechanism could aid in identifying molecular targets for the treatment of chronic airway remodeling and fibrosis in asthma.

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Section: Discussionmentioning

confidence: 68%

Opposing Actions of Stat1 and Stat6 on IL-13-Induced Up-Regulation of Early Growth Response-1 and Platelet-Derived Growth Factor Ligands in Pulmonary Fibroblasts

Ingram

Antao-Menezes

Mangum

et al. 2006

The Journal of Immunology

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“…Although both FAs and lysolecithin have been shown in vitro to have potentially toxic effects on endothelial cells, 2,33,34 others have suggested that LpL-mediated lipolysis 14 or LpL alone 16 may be antiinflammatory. Whether these conditions mimic those that occur in vivo is unknown.…”

Section: Discussionmentioning

confidence: 99%

In Vivo Arterial Lipoprotein Lipase Expression Augments Inflammatory Responses and Impairs Vascular Dilatation

Takáhashi

Hiyama

Yokoyama

et al. 2008

ATVB

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Objective-Although epidemiologic data suggest that hypertriglyceridemia and elevated plasma levels of fatty acids are toxic to arteries, in vitro correlates have been inconsistent. To investigate whether increased endothelial cell expression of lipoprotein lipase (LpL), the primary enzyme creating free fatty acids from circulating triglycerides (TG), affects vascular function, we created transgenic mice that express human LpL (hLpL) driven by the promoter and enhancer of the Tie2 receptor. Methods and Results-Mice expressing this transgene, denoted EC-hLpL and L for low and H for high expression, had decreased plasma TG levels compared with wild-type mice (WT): 106Ϯ31 in WT, 37Ϯ17 (line H), and 63Ϯ31 mg/dL (line L) because of a reduction in VLDL TG; plasma cholesterol and HDL levels were unaltered. Crossing a high expressing EC-hLpL transgene onto the LpL knockout background allowed for survival of the pups; TG in these mice was approximately equal to that of heterozygous LpL knockout mice. Surprisingly, under control conditions the EC-hLpL transgene did not alter arterial function or endothelial cell gene expression; however, after tumor necrosis factor (TNF)-␣ treatment, arterial vascular cell adhesion molecule-1 (VCAM-1), E-selectin, and endogenous TNF-␣ mRNA levels were increased and arteries had impaired endothelium-dependent vasodilatation. This was associated with reduced eNOS dimers. Conclusions-Therefore, we hypothesize that excess vascular wall LpL augments vascular dysfunction in the setting of inflammation. LpL is the rate-limiting enzyme for hydrolysis of plasma TG. LpL is synthesized by myocytes and adipocytes but is thought to function primarily on the luminal surface of endothelial cells. Therefore, along the arterial wall much of the exposure of endothelial cells to FAs is modulated by LpL actions.LpL has been suggested to have a dual effect on atherosclerosis development. 6 We and others have demonstrated that LpL contributes to lipid accumulation by stimulating the cellular binding and uptake of atherogenic lipoproteins in different vascular cell types including smooth muscle cells and macrophages. 7,8 Moreover, loss of macrophage LpL reduces atherosclerosis. 9 LpL acts as an activator of macrophage function, inducing TNF alpha (TNF-␣), 10 augmenting monocyte adhesion 11,12 and increasing phagocytosis in low glucose conditions. 13 Although these data suggest that LpL has atherogenic and inflammatory effects, there are contradictory data. LpL is reported to play an antiinflammatory role through generation of PPAR ligands for endothelial cells 14 and macrophages. 15 In human endothelial cells, LpL alone attenuated the inflammatory cascade produced by TNF-␣. 16 Thus, the function and role of LpL in inflammatory responses are not clear, but may vary depending on the in vitro conditions studied.To study the actions of LpL in arteries, we created mice with human LpL (hLpL) expression specifically in endothelial cells using the Tie2 promoter-enhancer 17 to drive an hLpL minigene. These transgenic mic...

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“…Previous reports indicate that LPC has immunomodulatory functions as it induces the expression of multiple genes relevant to inflammation including cytokines and chemokines, adhesion molecules, growth factors and proinflammatory enzymes in endothelial cells, smooth muscle cells, macrophages, and T-cells (Cieslik et al, 1998;Kume and Gimbrone, 1994;Kume et al, 1992;Morimoto et al, 2001;Nishi et al, 1998;Ochi et al, 1995;Oka et al, 2000;Sakata-Kaneko et al, 1998). LPC is also reported to inhibit expression of some genes in inflammatory responses including interferon g (IFNg)-induced Th1-cell-specific chemokines such as IFNg-inducible protein (10 kDa), monokine induced by IFNg and IFN-induced T-cella chemoattractant (Sheikh et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Lysophosphatidylcholine induces glial cell activation: Role of rho kinase

Sheikh

Nagai

Ryu

et al. 2008

Glia

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Lysophosphatidylcholine (LPC), a major phospholipid component of atherogenic oxidized LDL, is implicated in atherosclerosis and, recently, in neurodegenerative diseases. We investigated the immunomodulatory functions of LPC in the central nervous system (CNS) using both an in vivo rat model, and in vitro culture systems of human primary astrocytes and a microglia cell line, HMO6. Compared with PBS injection, 20 nmol LPC-injection into the rat striatum increased astrocyte and microglial accumulation and elevated iNOS expression; concomitantly a time-dependent decrease in number of neurons was exhibited. In vitro studies on astrocytes and HMO6 cells showed that LPC increased the gene expression of proinflammatory factors IL-1beta, COX-2, and GM-CSF. LPC also induced chemotactic responses in HMO6 cells. Inhibition of rho kinase by fasudil, Y27632, or expressing a dominant negative form of rho kinase inhibited the LPC-induced IL-1beta mRNA expression in both astrocytes and HMO6. Moreover, intraperitoneal fasudil injection inhibited the LPC-induced microglial accumulation and iNOS expression and also was effective in protecting against neuronal loss. Silencing G2A, a specific receptor for LPC, inhibited proinflammatory gene expression and HMO6 migration. Overall, our results indicate that LPC induced considerable neuroinflammatory reactivity in glia mediated by rho kinase-dependent pathways with inhibition of these pathways conferring significant extents of neuroprotection.

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Lysophosphatidylcholine Induces Early Growth Response Factor-1 Expression and Activates the Core Promoter of PDGF-A Chain in Vascular Endothelial Cells

Cited by 24 publications

References 64 publications

Opposing Actions of Stat1 and Stat6 on IL-13-Induced Up-Regulation of Early Growth Response-1 and Platelet-Derived Growth Factor Ligands in Pulmonary Fibroblasts

Opposing Actions of Stat1 and Stat6 on IL-13-Induced Up-Regulation of Early Growth Response-1 and Platelet-Derived Growth Factor Ligands in Pulmonary Fibroblasts

In Vivo Arterial Lipoprotein Lipase Expression Augments Inflammatory Responses and Impairs Vascular Dilatation

Lysophosphatidylcholine induces glial cell activation: Role of rho kinase

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