van Puijenbroek A A, Wissink S, van der Saag P T, Peppelenbosch M P
Hubrecht Laboratory, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.
Cytokine. 1999 Feb;11(2):104-10. doi: 10.1006/cyto.1998.0404.
Tumour necrosis factor (TNF) is a key regulator of inflammation and immunity. The cellular effects exerted by TNF depend, apart from NF-kappaB-directed gene transcription, largely on its ability to activate phospholipase A2(PLA2), yielding the release of arachidonic acid (AA) and its metabolites. AA metabolites, especially the leukotrienes, act as second messengers in TNF receptor signalling, as different inhibitors of AA metabolism impair a variety of TNF-induced biochemical events. The role, however, of AA and its metabolites in TNF-induced NF-kappaB activation is still obscure. Here we report that 4-bromophenacyl bromide (4-BPB; an inhibitor of PLA2), nordihydroguaretic acid (NDGA; a 5-lipoxygenase inhibitor), as well as MK-886 [an inhibitor of 5-lipoxygenase-activating protein (FLAP)] interfere with TNF-induced NF-kappaB-mediated transactivation. However, only 4-BPB inhibited the DNA-binding activity of NF-kappaB, whereas NDGA and MK-886 did not. Thus, different inhibitors interfere at different points in TNF-induced signalling leading to NF-kappaB-dependent transcription. Artificial induction of AA metabolism induced neither DNA-binding activity of NF-kappaB nor NF-kappaB-dependent transactivation. It was concluded that although TNF-induced signalling to NF-kappaB-dependent transcription is sensitive to inhibitors of AA metabolism at multiple points during this signalling, AA release is essential but not sufficient for NF-kappaB-activation.
肿瘤坏死因子（TNF）是炎症和免疫的关键调节因子。TNF所发挥的细胞效应，除了依赖于NF-κB介导的基因转录外，很大程度上还取决于其激活磷脂酶A2（PLA2）的能力，从而促使花生四烯酸（AA）及其代谢产物的释放。AA代谢产物，尤其是白三烯，在TNF受体信号传导中充当第二信使，因为AA代谢的不同抑制剂会损害多种TNF诱导的生化事件。然而，AA及其代谢产物在TNF诱导的NF-κB激活中的作用仍不清楚。在此我们报告，4-溴苯甲酰溴（4-BPB；一种PLA2抑制剂）、去甲二氢愈创木酸（NDGA；一种5-脂氧合酶抑制剂）以及MK-886 [一种5-脂氧合酶激活蛋白（FLAP）抑制剂] 会干扰TNF诱导的NF-κB介导的反式激活。然而，只有4-BPB抑制了NF-κB的DNA结合活性，而NDGA和MK-886则没有。因此，不同的抑制剂在TNF诱导的导致NF-κB依赖性转录的信号传导的不同点发挥作用。人工诱导AA代谢既未诱导NF-κB的DNA结合活性，也未诱导NF-κB依赖性反式激活。得出的结论是，尽管TNF诱导的向NF-κB依赖性转录的信号传导在该信号传导过程中的多个点对AA代谢抑制剂敏感，但AA释放对于NF-κB激活是必不可少的，但并不充分。
