Natural killer-sensitive targets stimulate production of TNF-alpha but not TNF-beta (lymphotoxin) by highly purified human peripheral blood large granular lymphocytes.
Natural killer-sensitive targets stimulate production of TNF-alpha but not TNF-beta (lymphotoxin) by highly purified human peripheral blood large granular lymphocytes.
复制标题
自然杀伤敏感靶点刺激高度纯化的人外周血大颗粒淋巴细胞产生 TNF-α，但不产生 TNF-β（淋巴毒素）。
作者：
P. Peters;J. Ortaldo;M. Shalaby;L. P. Svedersky;G. Nedwin;T. Bringman;P. Hass;B. Aggarwal;R. Herberman;D. Goeddel
高纯度的大颗粒淋巴细胞（LGL）群体已被证明介导自然杀伤（NK）细胞活性。NK细胞杀伤靶细胞的机制尚不明确;然而，据推测，这种杀伤可能涉及NK细胞产生和分泌的可溶性细胞毒性因子。所提供的数据表明，NK敏感的，但不NK耐药的肿瘤细胞系诱导高度纯化的人LGL群体产生具有细胞毒性和/或细胞抑制活性的因子。我们已经确定了这些因子之一，肿瘤坏死因子-α（TNF-α），并已表明，该因子的生产是由重组人干扰素-γ（rHuIFN-γ）增强。我们还研究了TNF-α在NK细胞的细胞毒性功能中的作用。数据显示，尽管高度纯化的LGL群体产生低水平的TNF-α，但这种淋巴因子对肿瘤靶细胞的细胞毒性/细胞抑制活性与高度纯化的LGL群体对肿瘤靶细胞的细胞毒性活性无关。此外，NK细胞介导的细胞毒性不能被针对重组人TNF-α和/或重组TNF-β（α光毒素）或rHuIFN-γ的各种表位的抗体可靠地抑制。这些数据表明，尽管TNF-α是由高度纯化的含NK的LGL细胞群产生的，但该因子似乎不负责NK细胞对经典NK靶细胞如Molt-4或K562的细胞毒性。我们认为，NK功能可以归因于多种因素的组合，而不是单一因素，并且至少有两个主要现象涉及LGL功能：导致经典体外NK测定中测量的细胞溶解的快速细胞毒性事件，例如针对K562;以及释放具有细胞毒性/细胞抑制活性的因子如TNF-α，其将抑制体内侵入肿瘤细胞的生长。
Highly purified populations of large granular lymphocytes (LGL) have been shown to mediate natural killer (NK) cell activity. The mechanism of target cell killing by NK cells is as yet undefined; however, it has been postulated that such killing may involve soluble cytotoxic factors produced and secreted by NK cells. The data presented show that NK-sensitive, but not NK-resistant, tumor cell lines induce highly purified populations of human LGL to produce factors with cytotoxic and/or cytostatic activities. We have identified one of these factors as tumor necrosis factor-alpha (TNF-alpha), and have shown that production of this factor is enhanced by recombinant human interferon-gamma (rHuIFN-gamma). We have also examined the role of TNF-alpha in the cytotoxic function of NK cells. The data show that although highly purified LGL populations produce low levels of TNF-alpha, the cytotoxic/cytostatic activity of this lymphokine on tumor target cells does not correlate with the cytotoxic activity of highly purified populations of LGL on tumor target cells. Furthermore, NK cell-mediated cytotoxicity is not reliably inhibited by antibodies directed against various epitopes of recombinant human TNF-alpha and/or recombinant TNF-beta (lymphotoxin) or rHuIFN-gamma. These data show that although TNF-alpha is produced by highly purified NK-containing LGL cell populations, this factor does not appear to be responsible for NK cell cytotoxicity against classical NK target cells such as Molt-4 or K562. We suggest that NK function can be attributed to a combination of factors rather than to a single factor alone, and that at least two major phenomena are involved in LGL function: the rapid cytotoxic events which lead to the cell lysis measured in classical in vitro NK assays such as against K562; and the release of factors such as TNF-alpha with cytotoxic/cytostatic activities which would inhibit the growth of invading tumor cells in vivo.