Published online before print December 7, 2006, doi: 10.1161/01.ATV.0000254672.04573.2d
© 2007 American Heart Association, Inc.
Vascular Biology |
Anthocyanin Prevents CD40-Activated Proinflammatory Signaling in Endothelial Cells by Regulating Cholesterol Distribution
From the Department of Nutrition, School of Public Health, Sun Yat-Sen University (Northern Campus), Guangzhou, PR China.
Correspondence to Wenhua Ling, MD, PhD, Professor, Dean, Department of Nutrition, School of Public Health, Sun Yat-Sen University (Northern Campus), Guangzhou, Guangdong Province, PR China 510080. E-mail lingwh{at}mail.sysu.edu.cn
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Abstract |
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Objective— Intracellular tumor necrosis factor receptor-associated factors (TRAFs) translocation to lipid rafts is a key element in CD40-induced signaling. The purpose of this study was to investigate the influence of anthocyanin on CD40-mediated proinflammatory events in human endothelial cells and the underlying possible molecular mechanism.
Methods and Results— Treatment of endothelial cells with anthocyanin prevented from CD40-induced proinflammatory status, measured by production of IL-6, IL-8, and monocyte chemoattractant protein-1 through inhibiting CD40-induced nuclear factor-
B (NF-B) activation. TRAF-2 played pivotal role in CD40–NF-B pathway as TRAF-2 small interference RNA (siRNA) diminished CD40-induced NF-B activation and inflammation. TRAF-2 overexpression increased CD40-mediated NF-B activation. Moreover, TRAF-2 almost totally recruited to lipid rafts after stimulation by CD40 ligand and depletion of cholesterol diminished CD40-mediated NF-B activation. Exposure to anthocyanin not only interrupted TRAF-2 recruitment to lipid rafts but also decreased cholesterol content in Triton X-100 insoluble lipid rafts. However, anthocyanin did not influence the interaction between CD40 ligand and CD40 receptor.
Conclusions— Our findings suggest that anthocyanin protects from CD40-induced proinflammatory signaling by preventing TRAF-2 translocation to lipid rafts through regulation of cholesterol distribution, which thereby may represent a mechanism that would explain the anti-inflammatory response of anthocyanin.
Intracellular tumor necrosis factor receptor-associated factors (TRAFs) translocation to lipid rafts is a key element in CD40-induced signaling. The purpose of this study was to investigate the influence of anthocyanin on CD40-mediated proinflammatory events in human endothelial cells and the underlying possible molecular mechanism.
Key Words: arteriosclerosis • cholesterol • endothelium • inflammation
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Introduction |
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Atherosclerosis possesses many features of chronic inflammation and is considered as an immuno-inflammatory disease.1 Several lines of evidence have demonstrated that the immune mediator CD40 and its counterpart CD40 ligand (CD40L) are potent activators in the initiation and development of this disease.2–4
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CD40 is a member of tumor necrosis factor (TNF) receptor superfamily that provides activation signals not only in antigen-presenting cells5–6 but also in a variety of nonimmune cells, including vascular cells like endothelial cells (ECs).7 Several studies have indicated that the cytoplasmic tail of CD40 lacks intrinsic catalytic activity and signals largely through its ability to recruit TNF receptor-associated factors (TRAFs), adapter proteins that bridge receptors of the TNF family to downstream signaling pathways. Of the 6 known mammalian TRAFs, TRAF-2 directly bind to a membrane-distal CD40 cytoplasmic domain and is thought to occupy a pivotal position in the signaling pathways initiated by CD40.8–11 Recent reports have described that CD40L stimulation of B cells renders TRAF-2 largely translocated in detergent-insoluble membrane microdomains or rafts, enriched in sphingolipids, cholesterol, and glycosylphosphatidylinositol-linked proteins.12,13 However, whether signals induced by CD40 also depends on these specialized membrane microdomains in vascular cells especially in ECs, which is related to atherogenesis, has not been analyzed in detail.
Anthocyanin is a large family of naturally occurring compounds and belongs to phytochemicals. Many studies have shown that it not only imparts color to plants but also exhibits pharmacological properties.14,15 Our recent study has demonstrated that anthocyanin promotes cholesterol efflux from macrophage-derived foam cells, suggesting that anthocyanin may possess potential function in regulating cholesterol distribution in cells.16 This let us speculate that anthocyanin may interfere with the recruitment of TRAF-2 in lipid rafts by changing cholesterol distribution and thus interrupts CD40-induced proinflammatory signaling. To confirm this speculation, we chose ECs, which are involved in leukocyte extravasation underlying inflammation, to evaluate the effect of anthocyanin on CD40-induced proinflammatory signaling pathway and uncover its relationship with lipid rafts.
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Materials and Methods |
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An expanded Materials and Methods section is available in the online data supplement at http://atvb.ahajournals.org.
Cell Culture
Human umbilical vein endothelial cells were isolated and used in this study.
Immunoprecipitation and Immunoblotting
Cellular lysates were immunoprecipitated and the protein complexes were washed and analyzed by immunoblotting using indicated antibody.
Luciferase Assay
After lysis, cellular extracts were assayed for luciferase activity using luciferase assay system.
Statistical Analysis
Data were analyzed statistically ANOVA followed by post-hoc statistical tests.
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Results |
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Anthocyanin Prevents CD40-Mediated Proinflammatory Response in Human ECs
To examine the effect of anthocyanin on CD40-induced endothelial cell activation, ECs were stimulated with CD40 cognate ligand-sCD40L (5 µg/mL) alone or in the presence of anthocyanin Cy-3-g or Pn-3-g for 24 hours. The inflammatory response was determined by measuring production of proinflammatory cytokines. Exposure to Cy-3-g or Pn-3-g dose-dependently inhibited CD40-induced endothelial release of IL-6 (supplemental Figure Ia, available online at http://atvb.ahajournals.org), IL-8 (supplemental Figure Ib), and MCP-1 (supplemental Figure Ic). The inhibitory effect of anthocyanin (100 µmol/L) in this model was essentially identical to that achieved by neutralizing anti-CD40 antibody. All these data evidenced that anthocyanin treatment prevented CD40-induced inflammation of ECs by recombinant CD40L.
Anthocyanin Inhibits CD40-Stimulated NF-B Activation at the Upstream of IB-
Phosphorylation and Blocks the Acquisition of a Proinflammatory EC Phenotype
We next investigated the effect of anthocyanin on NF-B activation by CD40, which is an important nuclear mediator in immune responses. Compared with control plasmid, transfection of ECs with human CD40 resulted in potent and significant induction of NF-B reporter activity, which was dose-dependently inhibited by Cy-3-g and Pn-3-g (Figure 1A).
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To avoid the limitations of transient transfection systems, we examined the function of anthocyanin in ECs activated by sCD40L. Cy-3-g and Pn-3-g treatment also reduced sCD40L-induced nuclear factor-B (NF-B) DNA binding activity in a concentration-dependent manner (Figure 1B). The inhibition of NF-B activation may, because of the interference by anthocyanin with the upstream level of IB- as anthocyanin, also concentration-dependently inhibited CD40-induced IB- activation (supplemental Figure IIa) and promoted IB- phosphorylation (supplemental Figure IIb).
To confirm the role of decreased NF-B activity in the inhibitory function of anthocyanin on EC activation, we used NF-B–specific decoy ODN and NF-B pharmacological blocker pyrrolidine dithiocarbamate. Pretreatment of ECs with NF-B decoy ODN (10 µmol/L) or pyrrolidine dithiocarbamate (10 µmol/L) led to the marked and significant reduction of CD40-induced cytokines secretion (data not shown).
These data indicated that reduction of CD40-mediated inflammation by anthocyanin may attribute to the inhibition of NF-B activation, which led to ECs acquired a proinflammatory phenotype.
TRAF-2 Is Essential for CD40-Induced Proinflammatory Signaling in ECs
Previous studies suggested that the intracellular signaling mediated by CD40 is regulated by a family of cytoplasmic adaptor molecules TRAFs, which connected TNF receptor to downstream signaling pathways.17–19 We focused our efforts on TRAF-2 to explore its role in CD40-mediated signaling.
We pretreated ECs with the specific siRNA against human TRAF-2 to investigate the effect of TRAF-2 depletion on CD40 signaling. TRAF-2 siRNA significantly decreased CD40-induced IL-6 (35.47% ± 12.38% reduction), IL-8 (30.79% ± 8.63% reduction), and MCP-1 (39.80% ± 4.82% reduction). The TRAF-2 siRNA did not influence PMA-mediated cytokine production in ECs (in which there is no evidence for TRAF-2 involvement, data not shown), demonstrating the specificity of siRNA to TRAF-2–mediated pathway in cytokine production. Compared with control siRNA, TRAF-2 siRNA also significantly reduced CD40-induced NF-B reporter (Figure 2A) and sCD40L-activated NF-B transcriptional activity (Figure 2B).
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To further investigate the casual role of TRAF-2 in modulation of CD40 signaling, we overexpressed TRAF-2 in ECs by transfecting human TRAF-2 construct. Overexpression of TRAF-2 potently enhanced CD40-mediated NF-B activation (supplemental Figure III). However, expression of dominant negative TRAF-2, which lacks zinc fingers but contains the C-terminal region essential for binding to CD40,18 almost completely diminished CD40-mediated NF-B DNA binding activity (supplemental Figure III), implying the critical role for TRAF-2 in CD40-mediated signal transduction. Collectively, all these data demonstrated that TRAF-2 is an essential and sufficient mediator of the CD40-activated inflammatory events in ECs.
Recruitment of TRAF-2 to Lipid Rafts During CD40 Signaling
Although TRAF-2 is critical to CD40 signaling, how TRAF-2 delivers the CD40-mediated signal to downstream is less understood An emerging evidence in cell surface receptor signaling is detergent-resistant liquid-ordered lipid membrane microdomains, or lipid rafts.20,21
To demonstrate the engagement of TRAF-2 in CD40 signaling, we used 3 separate approaches. First, we used immunoprecipitation to detect TRAF-2 interaction with CD40. In the unstimulated state, CD40 immunoprecipitates were not detected by TRAF-2 antibody (lane 1). CD40L stimulation resulted in obvious detection of TRAF-2 in CD40 immunoprecipitates (lane 2). Control experiments validated the nature of the TRAF-2 and CD40 immunoprecipitates (lane 3 and lane 4; supplemental Figure IV).
As a second approach, ECs were stimulated with sCD40L and the Triton X-100 insoluble/soluble pellets were isolated. As demonstrated in Figure 3A, all of TRAF-2 from unstimulated ECs (0 minutes) appeared in the detergent-soluble fraction. A significant translocation of TRAF-2 from soluble to insoluble fractions was already observed as early as 5 minutes after sCD40L addition and totally recruited to insoluble fraction after 10 minutes of stimulation, thereafter they progressively declined after 30 minutes.
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Next, we investigated the CD40–TRAF-2 signal transduction pathways by means of analysis of their signaling complexes. Additionally, we studied whether the signaling complex elicited by the engagement of endogenous CD40 occurred within or outside of microdomains. To this end, ECs were stimulated with Flag-tagged CD40L, lipid rafts were isolated, and the engaged CD40-TRAF-2 signaling complex were analyzed by immunoprecipitation using an anti-Flag antibody. For comparison, the total amount of receptor was immunoprecipitated by adding the ligand and anti-Flag antibody to the soluble and raft fractions of unstimulated cells. Before stimulation (0 minutes), TRAF-2 and CD40 complex was not formed and could not be detected in lipid rafts. On CD40L stimulation, the TRAF-2 and CD40 signaling complex was immediately formed and then completely translocated to lipid rafts in 5 minutes. The TRAF-2 complex was completely recruited to lipid rafts after 10 minutes (Figure 3B). Taken together, these observations provide strong evidence for the essential role of TRAF-2 recruitment to lipid rafts in CD40-mediated signal transduction.
Interference With Lipid Rafts Composition Induces the Switch of CD40 Signaling from NF-B Activation
Cholesterol has been postulated to be a crucial structural component of rafts.22 To demonstrate directly the involvement of lipid rafts in CD40 signaling, we used ß- MCD,23 which has been shown to be a useful tool in extracting cholesterol from biological membranes and disrupted membrane microdomains, to examine the role of lipid rafts in CD40-mediated NF-B activation. Disruption of lipid rafts by ß-MCD almost completely abrogated TRAF-2 engagement with CD40 (supplemental Figure Va, lane 2). This effect is not attributable to the loss of CD40 from this fraction with ß-MCD treatment alone (supplemental Figure Va, lane 3). Compared with untreated ECs (Figure 4, top), ß-MCD treatment also totally interrupted TRAF-2 translocation to lipid lipids after sCD40L stimulation (Figure 4, middle). However, -MCD, which is an inactive analogue of ß-MCD and unable to deplete cholesterol, was shown to exert no effect on CD40-induced TRAF-2 translocation (Figure 4, bottom). We next analyzed the effect of MCD on CD40-induced NF-B activation by monitoring the phosphorylation of IB-. NF-B activation was observed 5 minutes after stimulation of ECs with sCD40L, which was totally abolished by ß-MCD (supplemental Figure Vb, top). However, -MCD did not exert any impact on CD40-induced NF-B activation (supplemental Figure Vb, bottom). Collectively, these results suggested that interference with lipid rafts organization abolished TRAF-2 recruitment to this microdomain and switched its mediated signaling.
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Anthocyanin Blocks TRAF-2 Recruitment to Lipid Rafts Via Regulating Cholesterol Redistribution of Membrane Lipid Rafts
Next, the effect of anthocyanin on TRAF-2 recruitment to lipid rafts was examined. Notably, we found that anthocyanin Cy-3-g and Pn-3-g pretreatment before sCD40L stimulation dose-dependently decreased TRAF-2 recruitment in lipid rafts and increased TRAF-2 engagement in soluble fractions, indicating that anthocyanin blocked CD40- induced translocation of TRAF-2 to lipid rafts (Figure 5A).
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Having demonstrated that anthocyanin prevented CD40L-induced TRAF-2 recruitment in lipid rafts, we attempted to characterize the underlying possible molecular mechanism. To this point, we first designed to analyze whether anthocyanin may interfere with CD40L binding to CD40 receptor using flow cytometry. In unstimulated ECs, no detectable CD40L binding could be found, which was significantly augmented by stimulation of fluorescein isothiocyanate–CD40L. The interaction of CD40L with CD40 receptor was not influenced after addition of anthocyanin from 1 µmol/L to 100 µmol/L, excluding the possibility that anthocyanin inhibited CD40 signaling by interrupting ligand binding to receptor (supplemental Figure VI).
We further investigated the perturbing effect of anthocyanin on the membrane lipid rafts structure by determining the distribution of cholesterol in lipid rafts and soluble fractions. Anthocyanin slightly reduced cholesterol content from the soluble fraction (supplemental Figure VII), but efficiently and dose-dependently depleted cholesterol from the Triton X-100 insoluble lipid rafts (Figure 5B).
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Discussion |
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The major findings of our current study demonstrate that anthocyanin, namely, Cy-3-g and Pn-3-g, disrupts TRAF-2 recruitment to membrane lipid rafts by reducing cholesterol distribution in lipid rafts of membrane in human ECs. The depletion of TRAF-2 translocation by anthocyanin in the endothelial monolayer limits CD40-mediated activation of NF-
B, thus leading to the reduction of proinflammatory activation in ECs responsible to CD40 stimulation (Figure 6). CD40 signaling is a major trigger eliciting a proinflammatory reaction and promoting formation of atherosclerotic lesions.24–26 Inhibition of CD40-mediated inflammatory response by anthocyanin may thereby partially explain its anti-atherogenetic effects. To our knowledge, these results are the first demonstration of anthocyanin on the anti-inflammatory mode with respect to CD40 signaling in ECs. The data also further knowledge of intracellular signaling pathway that is activated by CD40 on ECs, particularly the role of lipid rafts.
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Today, multiple lines of evidence suggested that interaction of CD40 and its counterpart CD40L plays a crucial role in the onset and maintenance of inflammatory response, which is implicated in atherogenesis.27–30 Present study clearly shows that exposure of ECs to CD40 physiological ligand CD40L promotes functional cellular CD40 inflammatory signaling by increasing the release of IL-6, IL-8, and MCP-1. This effect is not attributable to the cytotoxicity of anthocyanin because the dosage of anthocyanin used in this experiment did not affect the cell viability or cause significant cytotoxicity on ECs which was determined by MTT cell proliferation assay, lactate dehydrogenase release assay, and trypan exclusion test (data not shown). These proinflammatory molecules then may attract direct T lymphocytes and macrophages to the atheroma and maintain chronic inflammation, promoting the initiation and progression of atherosclerotic lesion. It has been reported that CD40 signaling in ECs may be involved with activation of transcription mediators such as NF-B.7 In consistence with this concept, we find that transfection of CD40 plasmid or stimulation with sCD40L in ECs significantly increases NF-B reporter and DNA binding activity. Preexposure of ECs with NF-B decoy ODN or pyrrolidine dithiocarbamate interrupts CD40-induced cytokines production, indicating that NF-B activation is essential in CD40-mediated inflammation. NF-B belongs to a major family of transcriptional mediators, which are located in the intracellular nucleus. Because CD40 is a membrane receptor, question arises how the extracellular signals are tranduced from the cell surface to the nucleus activation.
Recent studies have demonstrated that TRAFs, including 6 TRAF proteins, associate with and transduce signals from TNF receptor family members, may act as an important adapter of proinflammatory signaling induced by CD40.17–19,31 TRAF-2 appears to interfere with CD40 signaling through activating NF-B DNA binding activity as TRAF-2 siRNA significantly reduced induction of NF-B activation and cytokines release by CD40. Overexpression of TRAF-2 in ECs leads to increased NF-B activation induced by CD40. Although the functions of TRAF proteins remain enigmatic, recent reports demonstrated that TRAF may associate with lipid rafts and then transduce signals from TNF receptor family members.12,17,21 But until now, the functional importance of lipid rafts in CD40-mediated signal transduction especially in vascular cells is still poorly understood. Remarkably, in this study, we found that sCD40L stimulation of ECs renders the rapid and dramatic recruitment of TRAF-2 bind to CD40 in the detergent-insoluble membrane microdomains or rafts. The microdomain integrity is essential for CD40-mediated NF-B activation since ß-MCD–mediated cholesterol depletion was shown to block the translocation of TRAF-2 molecule to lipid rafts and hampered their association with CD40. -MCD, which is unable to deplete cholesterol, exerts no effect on CD40-induced TRAF-2 translocation. Taken together, these findings suggest that CD40-mediated TRAF-2 interaction with lipid rafts components is critical for CD40-induced downstream proinflammatory events in ECs. However, the mechanism why the alteration of TRAF-2 translocation to lipid rafts affects CD40-mediated signaling remains unclear and needs further elucidation.
Anthocyanins are the most important plant pigments. Although in recent years, emerging reports have been evidenced the importance of anthocyanins as dietary antioxidants for prevention of oxidative damage, several studies gradually focused on the its anti-inflammatory effect.32,33 In the current study, we show that anthocyanin prevents CD40-induced inflammatory response via decreasing CD40-mediated NF-B activation. Anthocyanin treatment also inhibits CD40-induced translocation of TRAF-2 to lipid rafts in a dose-dependent fashion and this effect is not related to the impact of anthocyanin on CD40L binding to CD40 receptor. We then analyzed the effect of anthocyanin on the structure and composition of lipid rafts which is crucial for lipid rafts. More strikingly, we find that anthocyanin exposure significantly depletes cholesterol from the Triton X-100 insoluble lipid rafts, indicating strongly that anthocyanin blocks the translocation of TRAF-2 to lipid rafts in the cellular membrane and thus interrupts CD40-induced signaling.
In summary, we demonstrate that anthocyanin reduced cholesterol content in membrane insoluble lipid rafts in ECs, resulting in the decrease of TRAF-2 translocation to lipid recruitment and inhibition of CD40-induced inflammatory signaling pathway in ECs. These findings suggest that anthocyanin may act as a lipid-dependent regulator of inflammatory response and provide a novel insight into the therapeutic implications of anthocyanin in many chronic inflammatory-related diseases.
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Acknowledgments |
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Sources of Funding
This work was supported by the research grants from National Natural Science Foundation of China Research grants 30025037, 30371215, 30571568, China Medical Board of New York Inc (grant CMB 98-677), the National Basic Research Program (973 Program, No. 2006CB503902), and the Team Project of the Science Foundation of Guangdong Province.
Disclosures
None.
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Footnotes |
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Original received August 28, 2006; final version accepted November 19, 2006.
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