Overexpression of Interleukin-10 by Activated T Lymphocytes Inhibits Atherosclerosis in LDL Receptor–Deficient Mice by Altering Lymphocyte and Macrophage Phenotypes

Pinderski, Laura J.; Fischbein, Michael P.; Subbanagounder, Ganesamoorthy; Fishbein, Michael C.; Kubo, Nobuhiko; Cheroutre, Hilde; Curtiss, Linda K.; Berliner, Judith A.; Boisvert, William A.

doi:10.1161/01.res.0000018941.10726.fa

Cited by 321 publications

(216 citation statements)

References 47 publications

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“…Another possible explanation may be that AIF-1 overexpression biases the immune response from Th1 to Th2 as we have demonstrated in in vitro experiments (14) and in the trinitrobenzene sulphonateinduced colitis model in mice (15). Since atherosclerosis is aggravated in the Th1 condition, the Th2-biased immune deviation (elevation of IL-6 and IL-10 levels) may exert regulatory influences on atherogenesis in the AIF-1 Tg environment (32)(33)(34)(35)(36). However, AIF-1 transfectants also produce IL-12, a pro-atherogenic factor, upon stimulation with LPS (14).…”

Section: Discussionmentioning

confidence: 96%

Allograft inflammatory factor-1 augments macrophage phagocytotic activity and accelerates the progression of atherosclerosis in ApoE−/− mice

Mishima

Iwabuchi²,

Fujii

et al. 2008

Int J Mol Med

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Abstract. Allograft inflammatory factor (AIF)-1, originally cloned from a rat heart allograft under chronic rejection, is induced in various inflammatory conditions including atherosclerosis. Using mouse AIF-1 transfected macrophages and AIF-1 transgenic (AIF-1 Tg ) mice, we analyzed the influence of AIF-1 overexpression on macrophage phagocytosis and the development of atherosclerosis. The AIF-1 transfectants showed significantly increased phagocytosis of latex beads and E. coli BioParticles as well as incorporation of acetylated low-density lipoprotein (LDL) compared to those of vector controls. Concordant results were obtained with elicited peritoneal exudate cells from AIF-1 Tg mice. When AIF-1 Tg mice were crossbred with apolipoprotein E knockout mice (ApoE -/-), these AIF-1 Tg ApoE -/-mice developed significantly increased atherosclerotic lesions compared to ApoE -/-mice. These results suggest that enhanced AIF-1 expression leads to augmented incorporation of degenerated LDL by macrophages and promotes development of atherosclerotic vasculopathy.

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Section: Discussionmentioning

confidence: 96%

Allograft inflammatory factor-1 augments macrophage phagocytotic activity and accelerates the progression of atherosclerosis in ApoE−/− mice

Mishima

Iwabuchi²,

Fujii

et al. 2008

Int J Mol Med

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“…The evidence supporting the role for cholesterol in atherosclerosis is irrefutable because cholesterol contributes to the atherosclerotic lesion development [16]. For example, modified or oxidized LDL (oxLDL) can promote inflammatory processes in the arterial wall, activate monocytes or macrophages, increase free radical generation and lead to endothelial dysfunction [17]. Therefore, lowering of oxLDL levels by statins might contribute to some of the cholesteroldependent effects of statins.…”

Section: Clinical Trials With Statinsmentioning

confidence: 99%

Pleiotropic effects of statin therapy: molecular mechanisms and clinical results

Wang

Liu

Liao

2008

Trends in Molecular Medicine

537

394

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Statins inhibit the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which is required for cholesterol biosynthesis, and are beneficial in the primary and secondary prevention of cardiovascular disease. Most of the benefits of statin therapy are owing to the lowering of serum cholesterol levels. However, by inhibiting HMG-CoA reductase, statins can also inhibit the synthesis of isoprenoids, which are important lipid attachments for intracellular signaling molecules, such as Rho, Rac and Cdc42. Therefore, it is possible that statins might exert cholesterol-independent or 'pleiotropic' effects through direct inhibition of these small GTP-binding proteins. Recent studies have shown that statins might have important roles in diseases that are not mediated by cholesterol. Here, we review data from recent clinical trials that support the concept of statin pleiotropy and provide a rationale for their clinical importance. [6], have demonstrated the beneficial effects of statin therapy for primary and secondary prevention of cardiovascular disease. Because 60-70% of serum cholesterol is derived from hepatic synthesis and HMG-CoA reductase is the crucial, rate-limiting enzyme in the cholesterol biosynthetic pathway, inhibition of this enzyme by statins results in a dramatic reduction in circulating low-density lipoprotein (LDL)-cholesterol (Figure 1). In addition, reduction of LDL-cholesterol leads to upregulation of the LDL receptor and increased LDL clearance. The lowering of serum cholesterol levels is therefore thought to be the primary mechanism underlying the therapeutic benefits of statin therapy in cardiovascular disease [1]. Pleiotropy of statins: beyond cholesterol loweringStatins, however, might also exert cholesterol-independent or pleiotropic effects. By inhibiting the conversion of HMG-CoA to L-mevalonic acid, statins prevent the synthesis of important isoprenoids, such as farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP), which are precursors of cholesterol biosynthesis [7] (Figure 1). These intermediates serve as important lipid attachments for the post-translational modification of proteins, such as nuclear lamins, Ras, Rho, Rac and Rap [8]. These isoprenylated proteins constitute approximately 2% of total cellular proteins [9]. Protein isoprenylation (see Glossary) enables proper subcellular localization and trafficking of intracellular proteins. Given that isoprenylated proteins might

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“…IL-10 deactivates macrophages by downregulating the MHC class II molecule and preventing endocytosis which is conversely stimulated by IL-4 and IL-13 [29,30]. In part due to their anti-inflammatory profile, alternatively activated macrophages are believed to be protective against atherosclerosis although of these two alternatively activated sub-phenotypes, only IL-10 has shown consistent in vivo evidence of atheroprotection [31][32][33].…”

Section: Introductionmentioning

confidence: 99%

Macrophage heterogeneity and cholesterol homeostasis: Classically-activated macrophages are associated with reduced cholesterol accumulation following treatment with oxidized LDL

Chu¹,

Tai²,

Beer³

et al. 2013

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Macrophages are centrally involved during atherosclerosis development and are the predominant cell type that accumulates cholesterol in the plaque. Macrophages however, are heterogeneous in nature reflecting a variety of microenvironments and different phenotypes may be more prone to contribute towards atherosclerosis progression. Using primary human monocyte-derived macrophages, we sought to evaluate one aspect of atherogenic potential of different macrophage phenotypes by determining their propensity to associate with and accumulate oxidized low density lipoprotein (oxLDL). Classically-activated macrophages treated simultaneously with interferon γ (IFNγ) and tumour necrosis factor α (TNFα) associated with less oxLDL and accumulated less cholesterol compared to untreated controls. The combined treatment of IFNγ and TNFα reduced the mRNA expression of CD36 and the expression of both cell surface CD36 and macrophage scavenger receptor 1 (MSR1) protein. Under oxLDL loaded conditions, IFNγ and TNFα did not reduce macrophage protein expression of the transcription factor peroxisome proliferator-actived receptor γ (PPARγ) which is known to positively regulate CD36 expression. However, macrophages treated with IFNγ did prevent the PPARγ-specific agonist rosiglitazone from upregulating cell surface CD36 protein expression. Our results demonstrate that the observed reduction of cholesterol accumulation in macrophages treated with IFNγ and TNFα following oxLDL treatment was due at least in part to reduced cell surface CD36 and MSR1 protein expression.

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Overexpression of Interleukin-10 by Activated T Lymphocytes Inhibits Atherosclerosis in LDL Receptor–Deficient Mice by Altering Lymphocyte and Macrophage Phenotypes

Cited by 321 publications

References 47 publications

Allograft inflammatory factor-1 augments macrophage phagocytotic activity and accelerates the progression of atherosclerosis in ApoE−/− mice

Allograft inflammatory factor-1 augments macrophage phagocytotic activity and accelerates the progression of atherosclerosis in ApoE−/− mice

Pleiotropic effects of statin therapy: molecular mechanisms and clinical results

Macrophage heterogeneity and cholesterol homeostasis: Classically-activated macrophages are associated with reduced cholesterol accumulation following treatment with oxidized LDL

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