Stearic Acid and TNF-α Co-Operatively Potentiate MIP-1α Production in Monocytic Cells via MyD88 Independent TLR4/TBK/IRF3 Signaling Pathway.
Stearic Acid and TNF-α Co-Operatively Potentiate MIP-1α Production in Monocytic Cells via MyD88 Independent TLR4/TBK/IRF3 Signaling Pathway.
复制标题
DOI：
10.3390/biomedicines8100403
复制
发表时间：
2020-10-09
期刊：
影响因子：
4.7
通讯作者：
Ahmad R
中科院分区：
文献类型：
--
作者：
Kochumon S;Arefanian H;Azim R;Shenouda S;Jacob T;Abu Khalaf N;Al-Rashed F;Hasan A;Sindhu S;Al-Mulla F;Ahmad R
循环和脂肪组织中巨噬细胞炎性蛋白（MIP）-1α（CC基序趋化因子配体-3/CCL3）表达增加及其与肥胖状态下炎症的相关性已有充分的记录。由于肥胖与循环中硬脂酸和肿瘤坏死因子α（TNF-α）的增加有关，我们研究了硬脂酸和TNF-α是否共同调节人单核细胞中MIP-1α/CCL 3的表达，如果是这样，哪些信号通路参与了MIP-1α/CCL 3的调节。与单独的硬脂酸或TNF-α相比，硬脂酸和TNF-α处理单核细胞导致MIP-1α/CCL 3的产生增加。为了探讨其机制，我们通过TLR 4阻断降低硬脂酸对MIP-α/CCL 3表达的协同作用，意外地发现MyD 88敲除（KO）细胞中MIP-α/CCL 3的协同产生并没有受到抑制。相反，通过抑制TBK 1/IRF 3活性，这种MIP-α/CCL 3表达减弱。硬脂酸/TNF-α对MIP-1α/CCL 3的合成无协同作用。此外，多聚肌苷酸-多聚胞苷酸（poly I：C）激活IRF 3与TNF-α产生协同作用，产生MIP-1α/CCL 3，与硬脂酸相当。与瘦个体相比，肥胖个体在单核细胞中显示出高IRF 3表达。此外，肥胖个体脂肪组织中MIP-1α/CCL 3水平升高与TNF-α和CD 163呈正相关。总之，本研究为硬脂酸在存在与肥胖相关的TNF-α的情况下产生MIP-1α/CCL 3的病理作用提供了一种新的模型。
Increased circulatory and adipose tissue expression of macrophage inflammatory protein (MIP)-1α (CC motif chemokine ligand-3/CCL3) and its association with inflammation in the state of obesity is well documented. Since obesity is associated with increases in both stearic acid and tumor necrosis factor α (TNF-α) in circulation, we investigated whether stearic acid and TNF-α together could regulate MIP-1α/CCL3 expression in human monocytic cells, and if so, which signaling pathways were involved in MIP-1α/CCL3 modulation. Monocytic cells were treated with stearic acid and TNF-α resulted in enhanced production of MIP-1α/CCL3 compared to stearic acid or TNF-α alone. To explore the underlying mechanisms, cooperative effect of stearic acid for MIP-α/CCL3 expression was reduced by TLR4 blocking, and unexpectedly we found that the synergistic production of MIP-α/CCL3 in MyD88 knockout (KO) cells was not suppressed. In contrast, this MIP-α/CCL3 expression was attenuated by inhibiting TBK1/IRF3 activity. Cells deficient in IRF3 did not show cooperative effect of stearate/TNF-α on MIP-1α/CCL3 production. Furthermore, activation of IRF3 by polyinosinic-polycytidylic acid (poly I:C) produced a cooperative effect with TNF-α for MIP-1α/CCL3 production that was comparable to stearic acid. Individuals with obesity show high IRF3 expression in monocytes as compared to lean individuals. Furthermore, elevated levels of MIP-1α/CCL3 positively correlate with TNF-α and CD163 in fat tissues from individuals with obesity. Taken together, this study provides a novel model for the pathologic role of stearic acid to produce MIP-1α/CCL3 in the presence of TNF-α associated with obesity settings.
登录
查看更多内容
DOI：
10.1016/j.bbadis.2013.05.017
发表时间：
2014-03
影响因子：
6.2
作者：
Lee, Byung-Cheol;Lee, Jongsoon
通讯作者：
Lee, Jongsoon
影响因子：
5.2
作者：
Choe SS;Huh JY;Hwang IJ;Kim JI;Kim JB
通讯作者：
Kim JB
影响因子：
7.3
作者：
Kawasaki T;Kawai T
通讯作者：
Kawai T
DOI：
10.1016/j.biocel.2003.10.019
发表时间：
2004-10-01
影响因子：
4
作者：
Maurer, M;von Stebut, E
通讯作者：
von Stebut, E
影响因子：
7.7
作者：
Boden, G;She, PX;Ruderman, N
通讯作者：
Ruderman, N