Dbaibo G S, Obeid L M, Hannun Y A
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710.
J Biol Chem. 1993 Aug 25;268(24):17762-6.
Tumor necrosis factor-alpha (TNF-alpha) exerts pleiotropic biologic effects. Although TNF-alpha appears to activate a number of signal transduction pathways, the role of second messengers in mediating the different effects of TNF-alpha are not well defined. In this study, we investigated the role of ceramide as an intracellular mediator of TNF-alpha action. In Jurkat T cells, TNF-alpha caused early activation of the sphingomyelin cycle with peak hydrolysis of sphingomyelin observed at 30 min following addition of TNF-alpha. In this cell line, TNF-alpha caused potent activation of nuclear factor-kappa B (NF-kappa B) and exerted potent cytostatic/cytocidal activity. C2-ceramide mimicked the effects of TNF-alpha on cell growth in a dose-dependent manner, but C2-ceramide was unable to induce activation of NF-kappa B under multiple conditions investigated. C2-ceramide, however, enhanced activation of NF-kappa B in response to TNF-alpha with peak effects observed at a concentration of C2-ceramide of 5 microM. Thus, ceramide functions as a selective mediator of the cytostatic/cytotoxic effects of TNF-alpha and plays a positive feedback role in activation of NF-kappa B. TNF-alpha signaling, therefore, involves multiple second-messenger pathways that function independently or coordinately to transduce distinct functions of TNF-alpha.
肿瘤坏死因子-α（TNF-α）具有多种生物学效应。尽管TNF-α似乎能激活多种信号转导途径，但第二信使在介导TNF-α不同效应中的作用尚未明确界定。在本研究中，我们探究了神经酰胺作为TNF-α作用的细胞内介质的作用。在Jurkat T细胞中，TNF-α导致鞘磷脂循环的早期激活，在添加TNF-α后30分钟观察到鞘磷脂水解达到峰值。在该细胞系中，TNF-α导致核因子-κB（NF-κB）的有效激活并发挥强大的细胞生长抑制/细胞杀伤活性。C2-神经酰胺以剂量依赖的方式模拟了TNF-α对细胞生长的影响，但在多种研究条件下，C2-神经酰胺无法诱导NF-κB的激活。然而，C2-神经酰胺增强了TNF-α诱导的NF-κB激活，在C2-神经酰胺浓度为5微摩尔时观察到峰值效应。因此，神经酰胺作为TNF-α细胞生长抑制/细胞毒性效应的选择性介质发挥作用，并在NF-κB激活中起正反馈作用。因此，TNF-α信号传导涉及多个第二信使途径，这些途径独立或协同发挥作用以转导TNF-α的不同功能。
