Luteolin Inhibits Fibrillary β-Amyloid1–40-Induced Inflammation in a Human Blood-Brain Barrier Model by Suppressing the p38 MAPK-Mediated NF-κB Signaling Pathways
<p>Chemical structure of luteolin.</p> "> Figure 2
<p>Cytoprotective effects of luteolin on human brain microvascular endothelial cells (hBMECs), human astrocytes (hAs) and co-culture against fibrillary amyloid-β peptide 1-40 (fAβ<sub>1–40</sub>)-induced toxicity. (<b>A</b>) Luteolin increases cell viability of hBMECs as evaluated by a 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxy-phenyl)-2-(4-sulfophenyl)-2<span class="html-italic">H</span>-tetrazolium (MTS) assay. <span class="html-italic">n</span> = 8; (<b>B</b>) Luteolin increases cell viability of hAs as evaluated by MTS assay. <span class="html-italic">n</span> = 8; (<b>C</b>) Luteolin has a mild effect on cell viability of hBMECs in the co-culture as evaluated by Alamar blue assay. <span class="html-italic">n</span> = 6; (<b>D</b>) Luteolin influences cell viability of hAs in the co-culture as evaluated by Alamar blue assay. <span class="html-italic">n</span> = 6. Data are expressed as the mean ± standard error of mean (SEM); *** <span class="html-italic">p</span> < 0.001 vs. control; <sup>###</sup> <span class="html-italic">p</span> < 0.001 vs. fAβ<sub>1–40</sub>.</p> "> Figure 3
<p>Luteolin improves blood-brain barrier (BBB) function but does not scavenge intracellular reactive oxygen species (ROS) in co-culture against fAβ<sub>1–40</sub>-induced toxicity. (<b>A</b>) Luteolin decreased the transendothelial electrical resistance (TEER) value at concentrations of 10.0 μmol/L and 30.0 μmol/L; (<b>B</b>) Luteolin decreased the transendothelial permeability for fluorescein sodium (NaF) by preserving the reduction in value of the endothelial permeability coefficient (<span class="html-italic">Pe</span>) at a concentration of 30.0 μmol/L; (<b>C</b>) Luteolin decreased fluorescein isothioyanate labeled albumin (FITC-albumin) indicated by <span class="html-italic">Pe</span> value at a concentration of 30 μmol/L; (<b>D</b>) Luteolin does not reduce intracellular ROS levels in hBMECs and hAs in co-culture against fAβ<sub>1–40</sub>-induced toxicity. Data are expressed as mean ± SEM; <span class="html-italic">n</span> = 4; *** <span class="html-italic">p</span> < 0.001 vs. control; <sup>#</sup> <span class="html-italic">p</span> < 0.05; <sup>##</sup> <span class="html-italic">p</span> < 0.01; vs. fAβ<sub>1–40</sub>.</p> "> Figure 4
<p>Luteolin inhibits the release of inflammatory cytokines and the expression of cyclooxygenase-2 (COX-2) against fAβ<sub>1–40</sub>-induced toxicity. Luteolin decreased the levels of tumor necrosis factor α (TNF-α) (<b>A</b>); interleukin 1 β (IL-1β) (<b>B</b>); interleukin 6 (IL-6) (<b>C</b>) and interleukin 8 (IL-8) (<b>D</b>) in the basolateral supernatant and the levels of TNF-α (<b>E</b>); IL-1β (<b>F</b>); IL-6 (<b>G</b>); and IL-8 (<b>H</b>) in the apical supernatant collected at 48 h and 72 h time points following treatment with fAβ<sub>1–40</sub>. Data are expressed as the mean ± SEM; <span class="html-italic">n</span> = 4; ** <span class="html-italic">p</span> < 0.01; *** <span class="html-italic">p</span> < 0.001 vs. control; <sup>#</sup> <span class="html-italic">p</span> < 0.05; <sup>##</sup> <span class="html-italic">p</span> < 0.01; <sup>###</sup> <span class="html-italic">p</span> < 0.001 vs. fAβ<sub>1–40</sub>. Luteolin also down-regulated the expression of COX-2 in cell extracts of hBMECs (<b>I</b>) and hAs (<b>J</b>) of the co-culture after exposure to fAβ<sub>1–40</sub> for 72 h. Relative density values of COX-2 were quantified to intensity levels of β-actin (<b>K</b>). Data are expressed as the mean ± SEM, <span class="html-italic">n</span> = 4; *** <span class="html-italic">p</span> < 0.001 vs. control; <sup>###</sup> <span class="html-italic">p</span> < 0.001 vs. fAβ<sub>1–40</sub>.</p> "> Figure 5
<p>Luteolin suppresses mitogen-activated protein kinases (MAPKs) and nuclear factor κB (NF-κB) signaling pathways against fAβ<sub>1–40</sub>-induced toxicity. Representative immunoblots illustrate the expression of phosphorylated p38 (phosphor-p38), p38, phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2) (phosphor-ERK1/2), ERK1/2, phosphorylated c-Jun N-terminal kinase (phosphor-JNK), JNK, phosphorylated inhibitory κB kinase α/β (phosphor-IKKα/β), IKKα, IKKβ, inhibitory κB α (IκBα), phosphor-p65, and p65 in hBMECs (<b>A</b>) and hAs (<b>C</b>) extracts of the co-culture after exposure to fAβ<sub>1–40</sub> for 72 h. Quantitative analysis of the above-mentioned proteins by hBMECs (<b>B</b>) and hAs (<b>D</b>) was demonstrated. Data are expressed as the mean ± SEM; <span class="html-italic">n</span> = 3; *** <span class="html-italic">p</span> < 0.001 vs. control; <sup>##</sup> <span class="html-italic">p</span> < 0.01; <sup>###</sup> <span class="html-italic">p</span> < 0.001 vs. fAβ<sub>1–40</sub>.</p> "> Figure 6
<p>Effects of inhibition of p38 MAPK and NF-κB on the effect of luteolin on fAβ<sub>1–40</sub>-induced barrier dysfunction and inflammation. To block p38 MAPK and NF-κB pathways, co-cultures were treated with p38 MAPK inhibitor SB203580 (4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1<span class="html-italic">H</span>-imidazole, 10.0 μM) or NF-κB inhibitor PDTC (pyrrolidine dithiocarbamate, 20.0 μM) for 30 min prior to treatment with luteolin. Abolished effects of p38 MAPK and NF-κB inhibition of the effect of luteolin on TEER value (<b>A</b>); and production of TNF-α (<b>B</b>); IL-1β (<b>C</b>); IL-6 (<b>D</b>); and IL-8 (<b>E</b>) were seen by treatment with SB203580 or PDTC. Data are expressed as the mean ± SEM; <span class="html-italic">n</span> = 4; *** <span class="html-italic">p</span> < 0.001 vs. control; <sup>##</sup> <span class="html-italic">p</span> < 0.01; <sup>###</sup> <span class="html-italic">p</span> < 0.001 vs. fAβ<sub>1–40</sub>; <sup>&</sup> <span class="html-italic">p</span> < 0.05; <sup>&&</sup> <span class="html-italic">p</span> < 0.01 vs. luteolin combined with fAβ<sub>1–40</sub>; <sup>@</sup> <span class="html-italic">p</span> < 0.05; <sup>@@</sup> <span class="html-italic">p</span> < 0.01 vs. luteolin combined with fAβ<sub>1–40</sub>.</p> "> Figure 7
<p>Possible mechanisms by which luteolin inhibits fibrillary β-amyloid<sub>1–40</sub>-induced inflammation in a BBB model. AD: Alzheimer’s disease; Aβ stress: amyloid-β peptide induced cellular stress; NF-κB p65: nuclear factor κB p65 subunit; p-IκBα: phosphorylated inhibitory κB α.</p> ">
Abstract
:1. Introduction
2. Results
2.1. Luteolin Protects hBMECs, hAs, and Co-Culture against fAβ1–40-Induced Toxicity
2.2. Luteolin Improves BBB Function But Does Not Scavenge Intracellular Reactive Oxygen Species against fAβ1–40-Induced Toxicity
2.3. Luteolin Inhibits the Release of Inflammatory Cytokines and the Expression of COX-2 Against fAβ1–40-Induced Toxicity
2.4. Luteolin Inhibits NF-κB and MAPK Signal Pathways against fAβ1–40-Induced Toxicity
2.5. Involvement of the p38 MAPK/NF-κB Pathway in the Protective Effect of Luteolin on fAβ1–40-Induced Barrier Function and Inflammation
3. Discussion
4. Materials and Methods
4.1. Reagents
4.2. Cell Culture and Treatment
4.3. Co-Culture of hBMECs and hAs
4.4. MTS Cell Viability Assay
4.5. Alamar Blue Cell Viability Assay
4.6. TEER Measurement
4.7. Transendotheial Permeability Measurements
4.8. Enzyme-Linked Immunosorbent Assay for Proinflammatory Cytokines
4.9. Western Blot Analysis
4.10. Intracellular ROS Detection
4.11. Statistical Analysis
5. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Zhang, J.-X.; Xing, J.-G.; Wang, L.-L.; Jiang, H.-L.; Guo, S.-L.; Liu, R. Luteolin Inhibits Fibrillary β-Amyloid1–40-Induced Inflammation in a Human Blood-Brain Barrier Model by Suppressing the p38 MAPK-Mediated NF-κB Signaling Pathways. Molecules 2017, 22, 334. https://doi.org/10.3390/molecules22030334
Zhang J-X, Xing J-G, Wang L-L, Jiang H-L, Guo S-L, Liu R. Luteolin Inhibits Fibrillary β-Amyloid1–40-Induced Inflammation in a Human Blood-Brain Barrier Model by Suppressing the p38 MAPK-Mediated NF-κB Signaling Pathways. Molecules. 2017; 22(3):334. https://doi.org/10.3390/molecules22030334
Chicago/Turabian StyleZhang, Jun-Xia, Jian-Guo Xing, Lin-Lin Wang, Hai-Lun Jiang, Shui-Long Guo, and Rui Liu. 2017. "Luteolin Inhibits Fibrillary β-Amyloid1–40-Induced Inflammation in a Human Blood-Brain Barrier Model by Suppressing the p38 MAPK-Mediated NF-κB Signaling Pathways" Molecules 22, no. 3: 334. https://doi.org/10.3390/molecules22030334
APA StyleZhang, J. -X., Xing, J. -G., Wang, L. -L., Jiang, H. -L., Guo, S. -L., & Liu, R. (2017). Luteolin Inhibits Fibrillary β-Amyloid1–40-Induced Inflammation in a Human Blood-Brain Barrier Model by Suppressing the p38 MAPK-Mediated NF-κB Signaling Pathways. Molecules, 22(3), 334. https://doi.org/10.3390/molecules22030334