Kirchner Silvia, Boldt Simone, Kolch Walter, Haffner Silvia, Kazak Seran, Janosch Petra, Holler Ernst, Andreesen Reinhard, Eissner Günther
Department of Hematology, University of Regensburg, Regensburg, Germany.
J Leukoc Biol. 2004 Feb;75(2):324-31. doi: 10.1189/jlb.0703343. Epub 2003 Nov 11.
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.
肿瘤坏死因子的跨膜形式（mTNF）表达于活化的单核细胞（MO）和巨噬细胞（MPhi）上，能够诱导人内皮细胞（EC）凋亡。凋亡由两种不同机制介导：直接细胞接触和一种尚未鉴定的可溶性蛋白——死亡因子X。此外，mTNF作为一种受体，当与内皮细胞上的TNF受体结合时，会向MO/MPhi转导“反向信号”。mTNF的反向信号传导赋予对细菌脂多糖（LPS）的抗性。mTNF刺激反向信号传导会阻断MO/MPhi产生死亡因子X和促炎细胞因子的能力。我们研究了mTNF作为受体时使用哪些信号通路。反向信号传导触发两条独立的通路，可通过蛋白激酶C（PKC）抑制剂加以区分。LPS诱导的死亡因子X的抑制依赖于PKC，而LPS介导的细胞因子释放的抑制则不然。LPS和反向信号传导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激活反向信号传导会使MO/MPhi对随后LPS激活的MAPK/ERK通路产生抗性。因此，反向信号传导通过干扰关键信号转导通路在单核细胞中实现LPS抗性。
