School of Life Sciences and Biotechnology, Kyungpook National University, Daegu 702-701, Republic of Korea.
Cell Immunol. 2011;271(1):157-62. doi: 10.1016/j.cellimm.2011.06.019. Epub 2011 Jun 24.
Although Fas is known to be an apoptosis triggering molecule, accumulating studies indicate that Fas has non-apoptotic functions in certain cases. In an effort to identify the role of Fas in macrophage function, the human macrophage-like cell line THP-1 was analyzed after treatment with agonistic anti-Fas monoclonal antibody or co-incubation with FasL-expressing cells. Stimulation of Fas induced the expression of pro-inflammatory mediators such as matrix metalloproteinase (MMP)-9 and IL-8. The specificity of the reaction was confirmed by the transfection of Fas-specific siRNAs which resulted in a suppression of Fas expression as well as the responsiveness to the agonistic antibody. Utilization of various signaling inhibitors and ELISA-based NF-κB DNA binding assay demonstrated that the signaling initiated from Fas is mediated by mitogen activated protein kinases (MAPKs) including extracellular-signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) which induce subsequent activation of NF-κB. Furthermore, mixed cell culture experiment demonstrated that Fas can be activated through interaction with membrane-bound form of FasL during cell-to-cell interaction. These data indicate that Fas plays a role as an activation inducing molecule through interaction with its counterpart and Fas-mediate events are mediated by ERK/JNK MAPKs which subsequently activate NF-κB for the transcriptional activation of pro-inflammatory mediators.
尽管 Fas 是一种已知的凋亡触发分子，但越来越多的研究表明，Fas 在某些情况下具有非凋亡功能。为了确定 Fas 在巨噬细胞功能中的作用，分析了用激动型抗 Fas 单克隆抗体处理或与 FasL 表达细胞共孵育后的人巨噬细胞样细胞系 THP-1。Fas 的刺激诱导了促炎介质的表达，如基质金属蛋白酶 (MMP)-9 和白细胞介素-8。该反应的特异性通过 Fas 特异性 siRNA 的转染得到证实，这导致 Fas 表达的抑制以及对激动型抗体的反应性降低。利用各种信号转导抑制剂和基于 ELISA 的 NF-κB DNA 结合测定表明，从 Fas 起始的信号转导是由丝裂原激活的蛋白激酶 (MAPKs) 介导的，包括细胞外信号调节激酶 (ERK) 和 c-Jun N-末端激酶 (JNK)，它们诱导随后 NF-κB 的激活。此外，混合细胞培养实验表明，在细胞间相互作用过程中，Fas 可以通过与 FasL 的膜结合形式相互作用而被激活。这些数据表明，Fas 通过与配体相互作用作为一种激活诱导分子发挥作用，并且 Fas 介导的事件是由 ERK/JNK MAPKs 介导的，随后激活 NF-κB 以转录激活促炎介质。
