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首页> 外文期刊>Cellular Physiology and Biochemistry >Palmitate Activates CCL4 Expression in Human Monocytic Cells via TLR4/MyD88 Dependent Activation of NF-κB/MAPK/ PI3K Signaling Systems
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Palmitate Activates CCL4 Expression in Human Monocytic Cells via TLR4/MyD88 Dependent Activation of NF-κB/MAPK/ PI3K Signaling Systems

机译：棕榈酸酯通过TLR4 / MyD88依赖性激活NF-κB/ MAPK / PI3K信号系统激活人单核细胞中的CCL4表达

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Background/Aims Obesity is associated with adipose tissue inflammation which plays a key role in the development of insulin resistance and type 2 diabetes (T2D). Saturated free fatty acids (SFAs) levels are found to be elevated in obesity and T2D. Chemokines are known to have potent inflammatory functions in a wide range of biological processes linked to immunological disorders. Since CCL4 (Chemokine (C-C motif) ligand 4), also known as macrophage inflammatory protein-1β (MIP-1β), plays an important role in the migration of monocytes into the adipose tissue, we investigated the expression of CCL4 in monocytic cells/macrophages following activation with free fatty acid palmitate. Methods Human monocytic cell line THP-1 and macrophages derived from THP-1 and primary monocytes were stimulated with palmitate and LPS (positive control). CCL4 expression and secretion were measured with real time RT-PCR and ELISA respectively. Signaling pathways were identified by using THP-1-XBlueTM cells, THP-1-XBlueTM-defMyD cells, anti-TLR4 mAb and TLR4 siRNA. Results Palmitate induces CCL4 expression at both mRNA and protein levels in human monocytic cells. Palmitate-induced CCL4 production was markedly suppressed by neutralizing anti-TLR-4 antibody. Additionally, silencing of TLR4 by siRNA also significantly suppressed the palmitate-induced up-regulation of CCL4. MyD88-deficient cells did not express CCL4 in response to palmitate treatment. Inhibition of NF-kB and MAPK pathways suppressed the palmitate mediated induction of CCL4. Moreover, induction of CCL4 was blocked by PI3 Kinase inhibitors LY294002 and wortmannin. Conclusion Collectively, our results show that palmitate induces CCL4 expression via activation of the TLR4-MyD88/NF-kB/MAPK/ PI3K signaling cascade. Thus, our findings suggest that the palmitate-induced CCL4 production might be an underlying mechanism of metabolic inflammation.
机译：背景/目的肥胖与脂肪组织炎症有关，后者在胰岛素抵抗和2型糖尿病（T2D）的发生中起关键作用。发现肥胖症和T2D患者的饱和游离脂肪酸（SFA）水平升高。已知趋化因子在与免疫学疾病有关的广泛生物学过程中具有有效的炎症功能。由于CCL4（趋化因子（CC动机）配体4）（也称为巨噬细胞炎性蛋白1β（MIP-1β））在单核细胞向脂肪组织的迁移中起重要作用，因此我们研究了CCL4在单核细胞/用游离脂肪酸棕榈酸酯活化后的巨噬细胞。方法用棕榈酸酯和LPS（阳性对照）刺激人单核细胞系THP-1和源自THP-1的巨噬细胞以及原代单核细胞。实时RT-PCR和ELISA分别检测CCL4的表达和分泌。通过使用THP-1-XBlueTM细胞，THP-1-XBlueTM-defMyD细胞，抗TLR4 mAb和TLR4 siRNA识别信号通路。结果棕榈酸酯在人单核细胞中诱导mRNA和蛋白水平的CCL4表达。中和抗TLR-4抗体可显着抑制棕榈酸酯诱导的CCL4产生。另外，siRNA使TLR4沉默也显着抑制了棕榈酸酯诱导的CCL4上调。缺乏MyD88的细胞不响应棕榈酸酯治疗表达CCL4。 NF-kB和MAPK途径的抑制抑制了棕榈酸酯介导的CCL4的诱导。此外，PI3激酶抑制剂LY294002和渥曼青霉素阻止了CCL4的诱导。结论总体而言，我们的结果表明棕榈酸酯通过激活TLR4-MyD88 / NF-kB / MAPK / PI3K信号级联反应诱导CCL4表达。因此，我们的发现表明棕榈酸酯诱导的CCL4产生可能是代谢炎症的潜在机制。

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