Signaling pathways involved in LPS induced TNFalpha production in human adipocytes.
Signaling pathways involved in LPS induced TNFalpha production in human adipocytes.
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DOI：
10.1186/1476-9255-7-1
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发表时间：
2010-01-08
期刊：
影响因子：
--
通讯作者：
Festy F
中科院分区：
文献类型：
--
作者：
Hoareau L;Bencharif K;Rondeau P;Murumalla R;Ravanan P;Tallet F;Delarue P;Cesari M;Roche R;Festy F
肥胖的发展与炎症过程有关，脂肪组织在IL-6或TNFpha等促炎分子的分泌中的作用现在已得到很大程度的证实。虽然脂肪细胞分泌肿瘤坏死因子α可能是由TLR配体诱导的，但这种细胞因子的激活和分泌途径还不完全清楚。此外，鉴于巨噬细胞浸润是肥胖的一个特征，很难清楚地确定炎症期间脂肪组织中存在的不同细胞类型的参与程度。采用原代培养的人脂肪细胞和人外周血单核细胞。用病原体相关的分子模式处理细胞：在使用和不使用几种激酶抑制剂的情况下，使用LP。对细胞裂解产物进行p38MAP-Kinase蛋白印迹分析。RT-PCR法检测细胞内TNFpha基因的表达，ELISA法检测细胞培养上清液中TNFα蛋白的表达。我们首次发现，人类成熟脂肪细胞产生肿瘤坏死因子α主要依赖于两条途径：NFkappaB和p38 MAP Kinase。此外，我们还证明了PI3Kinase通路明显参与了内毒素途径的第一步。最后，我们发现与巨噬细胞相比，脂肪细胞能够分泌大量的肿瘤坏死因子α。这项研究清楚地表明，内毒素诱导的激活途径是与肥胖有关的炎症过程中不可或缺的一部分，脂肪细胞通过激活TLR4负责炎症脂肪组织中大部分分泌的TNFα。
The development of obesity has been linked to an inflammatory process, and the role of adipose tissue in the secretion of pro-inflammatory molecules such as IL-6 or TNFalpha has now been largely confirmed. Although TNFalpha secretion by adipose cells is probably induced, most notably by TLR ligands, the activation and secretion pathways of this cytokine are not yet entirely understood. Moreover, given that macrophagic infiltration is a characteristic of obesity, it is difficult to clearly establish the level of involvement of the different cellular types present within the adipose tissue during inflammation. Primary cultures of human adipocytes and human peripheral blood mononuclear cells were used. Cells were treated with a pathogen-associated molecular pattern: LPS, with and without several kinase inhibitors. Western blot for p38 MAP Kinase was performed on cell lysates. TNFalpha mRNA was detected in cells by RT-PCR and TNFalpha protein was detected in supernatants by ELISA assays. We show for the first time that the production of TNFalpha in mature human adipocytes is mainly dependent upon two pathways: NFkappaB and p38 MAP Kinase. Moreover, we demonstrate that the PI3Kinase pathway is clearly involved in the first step of the LPS-pathway. Lastly, we show that adipocytes are able to secrete a large amount of TNFalpha compared to macrophages. This study clearly demonstrates that the LPS induced activation pathway is an integral part of the inflammatory process linked to obesity, and that adipocytes are responsible for most of the secreted TNFalpha in inflamed adipose tissue, through TLR4 activation.
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发表时间：
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