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首页> 外文期刊>Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society >Transmembrane TNF-alpha mediates 'forward' and 'reverse' signaling, inducing cell death or survival via the NF-kappaB pathway in Raji Burkitt lymphoma cells.
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Transmembrane TNF-alpha mediates 'forward' and 'reverse' signaling, inducing cell death or survival via the NF-kappaB pathway in Raji Burkitt lymphoma cells.

机译：跨膜TNF-α介导Raji Burkitt淋巴瘤细胞中的“正向”和“反向”信号传导，通过NF-κB途径诱导细胞死亡或存活。

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摘要

Interestingly, some lymphoma cells, expressing high levels of transmembrane (tm)TNF-alpha, are resistant to secretory (s)TNF-alpha-induced necrosis but sensitive to tmTNF-alpha-mediated apoptosis. As tmTNF-alpha mediates "forward" as well as "reverse" signaling, we hypothesize that a balanced signaling between forward and reverse directions may play a critical role in determining the fate of cells bearing tmTNF-alpha. Using Raji cells as a model, we first added exogenous tmTNF-alpha on fixed, transfected NIH3T3 cells onto Raji cells to examine tmTNF-alpha forward signaling and its effects, showing that constitutive NF-kappaB activity and cellular inhibitor-of-apoptosis protein 1 transcription were down-regulated, paralleled with Raji cell death. As Raji cells express tmTNF-alpha, an inhibition of their tmTNF-alpha expression by antisense oligonucleotide caused down-regulation of NF-kappaB activity. Conversely, increasing tmTNF-alpha expression by suppressing expression of TNF-alpha-converting enzyme that cleaves tmTNF-alpha led to an enhanced activation of NF-kappaB, indicating that tmTNF-alpha, but not sTNF-alpha, contributes to constitutive NF-kappaB activation. We next transfected Raji cells with a mutant tmTNF-alpha lacking the intracellular domain to competitively suppress reverse signaling via tmTNF-alpha; as expected, constitutive NF-kappaB activity was decreased. In contrast, treating Raji cells with sTNFR2 to stimulate reverse signaling via tmTNF-alpha enhanced NF-kappaB activation. We conclude that tmTNF-alpha, when highly expressed on tumor cells and acting as a receptor, promotes NF-kappaB activation through reverse signaling, which is helpful to maintain tumor cell survival. On the contrary, tmTNF-alpha, when acting as a ligand, inhibits NF-kappaB activity through forward signaling, which is inclined to induce tumor cell death.
机译：有趣的是，一些表达高水平跨膜（tm）TNF-α的淋巴瘤细胞对分泌型（s）TNF-α诱导的坏死有抵抗力，但对tmTNF-α介导的凋亡敏感。由于tmTNF-α介导“正向”和“反向”信号传导，我们假设正向和反向之间的平衡信号传导可能在确定携带tmTNF-α的细胞的命运中起关键作用。以Raji细胞为模型，我们首先将固定转染的NIH3T3细胞上的外源性tmTNF-alpha添加到Raji细胞上，以检查tmTNF-alpha的正向信号传导及其作用，表明本构性NF-kappaB活性和细胞凋亡抑制蛋白1转录被下调，与此同时Raji细胞死亡。由于Raji细胞表达tmTNF-α，反义寡核苷酸对其tmTNF-α表达的抑制作用导致NF-κB活性下调。相反，通过抑制裂解tmTNF-alpha的TNF-alpha转换酶的表达来增加tmTNF-alpha的表达会导致NF-kappaB的激活增强，表明tmTNF-alpha而非sTNF-alpha有助于组成型NF-kappaB激活。接下来我们用缺少细胞内结构域的突变tmTNF-α转染Raji细胞，以竞争性地抑制通过tmTNF-α的反向信号传导。如预期的那样，组成型NF-κB活性降低。相反，用sTNFR2处理Raji细胞以刺激通过tmTNF-α的反向信号传导增强了NF-kappaB的激活。我们得出的结论是，tmTNF-α在肿瘤细胞上高表达并作为受体时，可通过反向信号促进NF-κB活化，这有助于维持肿瘤细胞的存活。相反，tmTNF-α作为配体时，会通过正向信号传导抑制NF-κB的活性，这可能会诱导肿瘤细胞死亡。

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