Granulocyte/macrophage Colony-stimulating Factor Plays an Essential Role in Oxidized Low Density Lipoprotein-induced Macrophage Proliferation

Biwa, Takeshi; Sakai, Masakazu; Shichiri, Motoaki; Horiuchi, Seikoh

doi:10.5551/jat1994.7.14

Cited by 23 publications

(15 citation statements)

References 29 publications

(6 reference statements)

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“…11 and 12). These findings are consistent with a model of macrophage proliferation within atherosclerotic plaques proposed by Biwa et al (11,12), wherein the initial effect of oxidized LDL may be to trigger (PKCand p110␥-dependent) synthesis and release of GM-CSF by resident macrophage/foam cells. Locally released GM-CSF then stimulates (class Ia PI3-kinase-dependent) proliferation of adjacent macrophages in an autocrine/paracrine manner.…”

Section: Discussionsupporting

confidence: 91%

“…The ability of oxidized LDL and atherogenic cytokines/ chemokines to trigger PI3-kinase signaling and Akt activation in inflammatory cells is well established (11,12,14). To determine whether p110␥ is the specific isoform of PI3-kinase involved in this pathway, we exposed BMDMs to these G protein-coupled receptor agonists and immunoblotted lysates with a phosphospecific antibody that recognizes activated Akt.…”

Section: Resultsmentioning

confidence: 99%

“…Two specific, structurally unrelated inhibitors of PI3-kinase, LY294002 and wortmannin, block the survival-promoting effect of oxidized LDL as well as phosphorylation of Akt, a major PI3-kinase-dependent antiapoptotic mediator. In addition to having a direct effect on macrophage survival, oxidized LDL plays a priming role in macrophage proliferation in atherosclerotic lesions by triggering the release of granulocyte/M-CSF (GM-CSF) via activation of PI3-kinase and protein kinase C (PKC) (11)(12)(13). GM-CSF release from macrophages in response to oxidized LDL induces proliferation in an autocrine or a paracrine fashion, suggesting that both the antiapoptotic and proliferative effects are PI3-kinase-dependent.…”

mentioning

confidence: 99%

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Deletion of the phosphoinositide 3-kinase p110γ gene attenuates murine atherosclerosis

Chang

Sukhova

Libby

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Inflammatory cell activation by chemokines requires intracellular signaling through phosphoinositide 3-kinase (PI3-kinase) and the PI3-kinase-dependent protein serine/threonine kinase Akt. Atherosclerosis is a chronic inflammatory process driven by oxidatively modified (atherogenic) lipoproteins, chemokines, and other agonists that activate PI3-kinase. Here we show that macrophage PI3-kinase/Akt is activated by oxidized low-density lipoprotein, inflammatory chemokines, and angiotensin II. This activation is markedly reduced or absent in macrophages lacking p110␥, the catalytic subunit of class Ib PI3-kinase. We further demonstrate activation of macrophage/foam cell PI3-kinase/Akt in atherosclerotic plaques from apolipoprotein E (apoE)-null mice, which manifest an aggressive form of atherosclerosis, whereas activation of PI3-kinase/Akt was undetectable in lesions from apoE-null mice lacking p110␥ despite the presence of class Ia PI3-kinase. Moreover, plaques were significantly smaller in apoE ؊/؊ p110␥ ؊/؊ mice than in apoE ؊/؊ p110␥ ؉/؉ or apoE ؊/؊ p110␥ ؉/؊ mice at all ages studied. In marked contrast to the embryonic lethality seen in mice lacking class Ia PI3-kinase, germ-line deletion of p110␥ results in mice that exhibit normal viability, longevity, and fertility, with relatively well tolerated defects in innate immune and inflammatory responses that may play a role in diseases such as atherosclerosis and multiple sclerosis. Our results not only shed mechanistic light on inflammatory signaling during atherogenesis, but further identify p110␥ as a possible target for pharmacological intervention in the primary and secondary prevention of human atherosclerotic cardiovascular disease.Akt ͉ inflammation ͉ macrophage ͉ lipoproteins ͉ G protein-coupled receptors

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Section: Discussionsupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Deletion of the phosphoinositide 3-kinase p110γ gene attenuates murine atherosclerosis

Chang

Sukhova

Libby

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…Both G-CSF and GM-CSF stimulate the mobilization and proliferation of monocytes and macrophages. [21][22][23][24][25][26][27] GM-CSF and G-CSF also have direct effects on vascular smooth muscle migration 28,29 and neutrophil activation. 22 These potentially harmful effects may outweigh the putative benefits of these agents.…”

Section: Serum Lipid Levelsmentioning

confidence: 99%

Granulocyte Colony-Stimulating Factor and Granulocyte Macrophage Colony-Stimulating Factor Exacerbate Atherosclerosis in Apolipoprotein E–Deficient Mice

et al. 2007

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Background— Recent studies have suggested a potential contribution of bone marrow–derived progenitor cells to vascular repair. Preliminary clinical studies have explored the possibility that mobilization of progenitor cells with granulocyte macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) can affect vascular repair. However, it is not known whether the short-term administration of G-CSF or GM-CSF exerts beneficial effects on atherosclerosis. Methods and Results— Apolipoprotein E–deficient mice were treated with either GM-CSF or G-CSF at a dose of 10 μg · kg −1 · d −1 SC administered daily for 5 days per week on alternating weeks for a total of 20 doses over an 8-week treatment period. We found that in animals maintained on a high-fat diet, both G-CSF and GM-CSF actually demonstrated an increase in atherosclerotic lesion extent. The increase in atherosclerotic extent was not associated with an increase in either inflammatory cells or expression of proinflammatory genes. Interestingly, adventitial vascularity significantly increased, suggesting a mechanistic role for vasa vasorum neovascularization. Conclusions— These findings demonstrate that in this animal model of atherosclerosis, not only did administration of G-CSF or GM-CSF fail to demonstrate any beneficial therapeutic effect, but both resulted in a worsening of atherosclerosis.

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“…40 IL-6 and IL-8 were significantly increased in infarct-related coronary artery thrombi and atherosclerotic plaque specimens obtained with a transluminal extraction catheter from cases of acute myocardial infarction. 41 Moreover, GM-CSF was demonstrated to be an important factor in oxidized LDL-induced macrophage proliferation, 42 and Gupta et al found that IFN-␥ potentiated atherosclerosis in ApoE knockout mice. 43 Because release of IL-6, IL-8, and IFN-␥ was also observed in C pneumoniae-infected macrophages, these molecules may play an important role in the host defense against C pneumoniae.…”

Section: Discussionmentioning

confidence: 99%

Simvastatin Reduces Chlamydophila pneumoniae –Mediated Histone Modifications and Gene Expression in Cultured Human Endothelial Cells

Schmeck

Beermann

N′Guessan

et al. 2008

Circulation Research

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Abstract-Inflammatory activation of the endothelium by Chlamydophila pneumoniae infection has been implicated in the development of chronic vascular lesions and coronary heart disease by seroepidemiological and animal studies. We tested the hypothesis that C pneumoniae induced inflammatory gene expression is regulated by Rho-GTPase-related histone modifications. C pneumoniae infection induced the liberation of proinflammatory interleukin-6, interleukin-8, granulocyte colony-stimulating factor, macrophage inflammatory protein-1␤, granulocyte/macrophage colonystimulating factor, and interferon-␥ by human endothelial cells. Cytokine secretion was reduced by simvastatin and the specific Rac1 inhibitor NSC23766 but was synergistically enhanced by inhibitors of histone deacetylases trichostatin A and suberoylanilide hydroxamic acid. Infection of endothelial cells with viable C pneumoniae, but not exposure to heat-inactivated C pneumoniae or infection with C trachomatis, induced acetylation of histone H4 and phosphorylation and acetylation of histone H3. Pretreatment of C pneumoniae-infected cells with simvastatin or NSC23766 reduced global histone modifications as well as specific modifications at the il8 gene promoter, as shown by chromatin immunoprecipitation. Reduced recruitment of nuclear factor B p65/RelA as well as of RNA polymerase II was observed in statin-treated cells. Taken together, Rac1-mediated histone modifications seem to play an important role in C pneumoniae-induced cytokine production by human endothelial cells. Key Words: endothelial cells Ⅲ cytokines Ⅲ statins Ⅲ Chlamydophila pneumoniae Ⅲ histones C hlamydia are Gram-negative bacteria that are obligate intracellular parasites of eukaryotic cells, including endothelial cells. Although chronic or recurrent infections with Chlamydophila pneumoniae have been associated with the development of vascular lesions and atherosclerosis, little is known about the molecular pathogenesis. [1][2][3][4] Infection of endothelial cells with C pneumoniae may initiate and perpetuate local inflammation by inducing cytokine release (eg, interleukin [IL]-6, IL-8) and adhesion molecule expression (P-/E-selectin, intercellular adhesion molecule-1, vascular cell adhesion molecule-1), which subsequently results in recruitment of inflammatory cells to the endothelium. 5,6 Infection of the endothelium by Chlamydia is recognized by different pattern-recognition receptors. Membrane-bound Toll-like receptors TLR2 and TLR4 have been demonstrated to mediate host defense against C pneumoniae or chlamydial components. [7][8][9][10] In addition, the nucleotide-binding oligomerization domain protein NOD1 was identified as part of a cytosolic surveillance system detecting intracellular Chlamydia in human endothelial cells. 11 The detection of pathogens by these pattern-recognition receptors resulted in the activation of complex signaling pathways, including the stimulation of nuclear factor (NF)-B-dependent gene transcription. 12 Increasing evidence indicates that histone modificatio...

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Granulocyte/macrophage Colony-stimulating Factor Plays an Essential Role in Oxidized Low Density Lipoprotein-induced Macrophage Proliferation

Cited by 23 publications

References 29 publications

Deletion of the phosphoinositide 3-kinase p110γ gene attenuates murine atherosclerosis

Deletion of the phosphoinositide 3-kinase p110γ gene attenuates murine atherosclerosis

Granulocyte Colony-Stimulating Factor and Granulocyte Macrophage Colony-Stimulating Factor Exacerbate Atherosclerosis in Apolipoprotein E–Deficient Mice

Simvastatin Reduces Chlamydophila pneumoniae –Mediated Histone Modifications and Gene Expression in Cultured Human Endothelial Cells

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