Apolipoprotein E Inhibition of Proliferation of Mitogen-Activated T Lymphocytes: Production of Interleukin 2 with Reduced Biological Activity

Kelly, Michael E.; Clay, Moira A.; Mistry, Meenakshi J.; Hsieh-Li, Hsiu Mei; Harmony, Judith A.K.

doi:10.1006/cimm.1994.1302

Cited by 118 publications

(87 citation statements)

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“…As an increased WC and an increased WHR are associated with abdominal obesity, this finding could suggest that in obese subjects TNF-a may be mostly secreted locally by intra-abdominal adipose tissue and may not reach circulation while TNFR2 does. Local and intra-abdominal adipose tissue secretion of TNF-a has been reported by Mohamed-Ali 55 and is consistent with an autocrin and paracrin and not endocrin secretion of TNF-a by adipose tissue. 17 Our results are in agreement with Hotamisligil results 15 suggesting that serum TNFR2 level could be a better marker of insulin resistance-related obesity than TNF-a level since HOMA strongly correlates with TNFR2 and not with TNF-a.…”

Section: Discussionsupporting

confidence: 87%

“…It is not possible to conclude if it is a reduced apoE level in obese adults which leads in part to low grade inflammation, expressed by increased CRP level or, inversely, if it is low grade systemic inflammation which leads to reduced apoE level. However, in vitro cellular studies have suggested an anti-proliferative role of apoE on T lymphocytes, 45,55 smooth muscle cells 44,46 and microglia. 47 Indirect in vivo anti-inflammatory role of apoE has also been suggested in apoE knock-out mice model.…”

Section: Discussionmentioning

confidence: 99%

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Negative and independent influence of apolipoprotein E on C-reactive protein (CRP) concentration in obese adults. Potential anti-inflammatory role of apoE in vivo

et al. 2001

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BACKGROUND: Obesity is frequently associated with an increase in the early inflammation marker C-reactive protein (CRP), insulin resistance and changes in lipoprotein metabolism. Increased CRP is known as an independent cardiovascular risk factor. Since the apolipoproteins (apo) E and CIII components of HDL are associated with reduced cardiovascular risk and since apoE has in vitro anti-inflammatory effect, we have investigated the relationships between apoE, apoCIII (in apoB and non apoB containing lipoproteins) and CRP in obese adults. METHODS:The following parameters from 34 healthy obese fasting women (age 22 -64 y, body mass index (BMI) 28 -68 kg=m 2 ) were measured: (1) ApoE and apoCIII, in total plasma, in apoB-(E LpB, CIII LpB) and non-apoB-containing lipoproteins (E LpnonB, CIII LpnonB); (2) CRP and cytokine secreted by adipose tissue (TNF-a and its soluble receptor TNFR2); (3) triglyceride, HDL-cholesterol, systolic blood pressure, diastolic blood pressure, waist and hip circumferences, insulin, glucose. HOMA, a marker of insulin sensitivity, and the ratio E=CIII in LpB and LpnonB were calculated. RESULTS: CRP was positively correlated with BMI (P < 0.05), waist circumference (WC, P < 0.05), triglyceride (P < 0.05) and negatively correlated with apoE (P < 0.01) and E LpnonB (P < 0.05). Two multiple regression models including parameters related to CRP with a P < 0.25 were run stepwise to assess their independent contribution to CRP concentration. In the first model (including BMI, WC, HOMA, insulin, triglyceride, apoE, E LpnonB), apoE was the best predictor of CRP (P ¼ 0.01) together with triglyceride (P ¼ 0.02) and BMI (P ¼ 0.08). The second model took into account E=CIII LpnonB ratio with the parameters included in the first model. In this second model, E=CIII LpnonB was the best predictor of CRP (P ¼ 0.007), explaining 39% of CRP variance. CONCLUSION: ApoE is strongly correlated with CRP and could have an anti-inflammatory effect in vivo in obese subjects. This correlation could be limited to LpnonB lipoproteins, depending on their apoE and CIII relative content.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Negative and independent influence of apolipoprotein E on C-reactive protein (CRP) concentration in obese adults. Potential anti-inflammatory role of apoE in vivo

et al. 2001

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“…The copy number fell significantly on day 56 in all groups, but much more so in the FGAd vector co-treated groups ( Figure 6i, lanes 2 and 4) than in HDAd vector co-treated groups (Figure 6i, lanes 1 and 3). As APOE has been reported to display immunomodulatory properties, 24,25 we treated mice with an FGAdexpressing mouse very-low-density lipoprotein receptor (VLDLR). VLDLR is normally expressed in APOA1 À/À mice and its induced overexpression does not induce a humoral immune response.…”

Section: Co-injection Of Fgad Suppresses Hdad-mediated Apoa1 Expressionmentioning

confidence: 99%

Sustained phenotypic correction in a mouse model of hypoalphalipoproteinemia with a helper-dependent adenovirus vector

et al. 2006

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We examined the efficacy and host response to the adenovirus (Ad)-mediated delivery of human apolipoprotein A-I (APOA1) gene to the liver of APOA1 À/À mice. Administration of a first-generation vector (FGAd-AI) resulted in a transient appearance of APOA1 in plasma and induced an anti-APOA1 antibody titer, whereas treatment with a helperdependent vector (HDAd-AI) resulted in sustained APOA1 expression without inducing an antibody titer. With these results, we studied the effects of FGAd vectors on APOAI expression by HDAd-AI vector. Co-treatment with an FGAd vector inhibited HDAd-AI-mediated APOA1 expression independent of transgene cassettes, but only FGAd-AI induced a humoral response. Furthermore, APOA1 mRNA levels in mice co-treated with FGAd vectors were much lower than those expected from the vector copy number, suggesting that DNA of FGAd vectors interferes with the HDAd-AI vector's APOA1 promoter. A single treatment with an HDAd-AI vector produced a supraphysiological plasma APOA1 level that gradually declined to about half the normal human level over the course of 2 years, associated with a plasma cholesterol level that is persistently higher than that in controls. This investigation provides the proof of principle that liver-directed HDAd gene delivery is effective for the long-term phenotypic correction of monogenic hypoalphalipoproteinemia.

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“…When apoE is added to mitogen-treated lymphocytes and monocytes/macrophages, two readouts of Th cell responsiveness are reduced: proliferation, and production of IL-2 (T cell growth factor) (11). In addition, apoE suppresses human T lymphocyte proliferation ex vivo, independent of the T cell mitogen used (12).…”

mentioning

confidence: 99%

Apolipoprotein E and Peptide Mimetics Modulate Inflammation by Binding the SET Protein and Activating Protein Phosphatase 2A

Christensen

Ohkubo

Oddo

et al. 2011

The Journal of Immunology

107

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The molecular mechanism by which apolipoprotein E (apoE) suppresses inflammatory cytokine and NO production is unknown. Using an affinity purification approach, we found that peptide mimetics of apoE, derived from its receptor binding domain residues 130–150, bound to the SET protein, which is a potent physiological inhibitor of protein phosphatase 2A (PP2A). Both holo-apoE protein and apoE-mimetic peptides bound to the C-terminal region of SET, which is then associated with an increase in PP2A-mediated phosphatase activity. As physiological substrates for PP2A, the LPS-induced phosphorylation status of signaling MAPK and Akt kinase is reduced following treatment with apoE-mimetic peptides. On the basis of our previous report, in which apoE-mimetic peptides reduced I-κB kinase and NF-κB activation, we also demonstrate a mechanism for reduced production of inducible NO synthase protein and its NO product. These data provide evidence for a novel molecular mechanism by which apoE and apoE-mimetic peptides antagonize SET, thereby enhancing endogenous PP2A phosphatase activity, which reduces levels of phosphorylated kinases, signaling, and inflammatory response.

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Apolipoprotein E Inhibition of Proliferation of Mitogen-Activated T Lymphocytes: Production of Interleukin 2 with Reduced Biological Activity

Cited by 118 publications

References 0 publications

Negative and independent influence of apolipoprotein E on C-reactive protein (CRP) concentration in obese adults. Potential anti-inflammatory role of apoE in vivo

Negative and independent influence of apolipoprotein E on C-reactive protein (CRP) concentration in obese adults. Potential anti-inflammatory role of apoE in vivo

Sustained phenotypic correction in a mouse model of hypoalphalipoproteinemia with a helper-dependent adenovirus vector

Apolipoprotein E and Peptide Mimetics Modulate Inflammation by Binding the SET Protein and Activating Protein Phosphatase 2A

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