LPS resistance in monocytic cells caused by reverse signaling through transmembrane TNF (mTNF) is mediated by the MAPK/ERK pathway
LPS resistance in monocytic cells caused by reverse signaling through transmembrane TNF (mTNF) is mediated by the MAPK/ERK pathway
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DOI：
10.1189/jlb.0703343
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发表时间：
2004-02-01
影响因子：
5.5
通讯作者：
Eissner, G
中科院分区：
文献类型：
--
作者：
Kirchner, S;Boldt, S;Eissner, G
表达于活化的单核细胞(MO)和巨噬细胞(MPhi)上的跨膜型肿瘤坏死因子(MTnf)能够诱导人内皮细胞(EC)的凋亡。细胞凋亡由两种不同的机制介导：直接细胞接触和一种尚不确定的可溶性蛋白-死亡因子X。此外，mtnf作为一种受体，在与EC上的肿瘤坏死因子受体结合时，将“反向信号”传递给MO/MPhi。Mtnf的反向信号增强了对细菌脂多糖(LPS)的抗性。Mtnf对反向信号的刺激阻断了MO/MPhi产生死亡因子X和促炎细胞因子的能力。我们已经研究了mtnf作为受体使用了哪些信号通路。反向信号触发两条独立的通路，这两条通路可以被蛋白激酶C(PKC)抑制剂区分开来。抑制内毒素诱导的死亡因子X依赖于PKC，而抑制内毒素介导的细胞因子释放则不依赖于PKC。内毒素和反向信号刺激丝裂原活化蛋白激酶(MAPK)/细胞外信号调节激酶(ERK)通路。有趣的是，mtnf激活反向信号使MO/MPhi不能被内毒素激活MAPK/ERK通路。因此，反向信号通过干扰关键的信号转导通路在单核细胞中实现对内毒素的抵抗。
The transmembrane form of tumor necrosis factor (mTNF), expressed on activated monocytes (MO) and macrophages (MPhi), is able to induce apoptosis in human endothelial cells (EC). Apoptosis is mediated by two distinct mechanisms: direct cell contact and a yet-unidentified soluble protein, death factor X. In addition, mTNF acts as a receptor that transduces a "reverse signal" into MO/MPhi when bound to the TNF receptor on EC. Reverse signaling by mTNF confers resistance to bacterial lipopolysaccharide (LPS). Stimulation of reverse signaling by mTNF blocks the ability of MO/MPhi to produce death factor X and proinflammatory cytokines. We have investigated which signaling pathways are used by mTNF acting as receptor. Reverse signaling triggers two independent pathways that can be distinguished by protein kinase C (PKC) inhibitors. The suppression of LPS-induced death factor X is dependent on PKC, whereas the suppression of LPS-mediated cytokine release is not. LPS and reverse signaling stimulate the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway. It is interesting that the activation of reverse signaling by mTNF renders MO/MPhi refractory to a subsequent activation of the MAPK/ERK pathway by LPS. Thus, reverse signaling achieves LPS resistance in monocytic cells through interference with key signal-transduction pathways.