Cytokine dependent inverse regulation of CD54 (ICAM1) and major histocompatibility complex class I antigens by nuclear factor κB in HEp2 tumor cell line:: Effect on the function of natural killer cells
Cytokine dependent inverse regulation of CD54 (ICAM1) and major histocompatibility complex class I antigens by nuclear factor κB in HEp2 tumor cell line:: Effect on the function of natural killer cells
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DOI：
10.1016/s0198-8859(03)00039-9
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发表时间：
2003-05-01
期刊：
影响因子：
2.7
通讯作者：
Park, NH
中科院分区：
文献类型：
--
作者：
Jewett, A;Wang, MY;Park, NH
本研究的目的是探讨HEp 2细胞中核因子κ B（NF κ B）活性升高可调节免疫效应细胞功能和存活的机制。通过IkappaB超阻遏物的稳定表达抑制NF κ B功能活性使得HEp 2细胞（HEp 2-IkappaB（（S32 AS 36 A）对自然杀伤（NK）细胞介导的细胞毒性敏感。当用IFN-γ处理HEp 2-IkappaB（（S32 AS 36 A））细胞时，这些细胞的表面ICAM 1表达的增加大于单独载体转染的HEp 2细胞的表面。相比之下，肿瘤坏死因子α（TNF-α）处理增加了ICAM-1在单独载体转染的HEp 2细胞表面的表达，而不是在HEp 2-IkappaB（（S32 AS 36 A））细胞表面的表达。此外，在HEp 2-IkappaB（（S32 AS 36 A））细胞的表面上，通过TNF-α和干扰素-γ（IFN-γ）处理的组合的ICAM-1的协同增强被完全消除。ICAM-1表面抗原的封闭抗体可部分抑制IL-2处理的NK细胞对HEp 2-IkappaB（（S32 AS 36 A））细胞的杀伤作用。与ICAM-1相反，在HEp 2细胞中，当核NF κ B的功能被抑制时，主要组织相容性复合物（MHC）I类抗原的表达下调。向HEp 2-kappaB（（S32 AS 36 A））细胞中添加IFN-γ增加了MHC I类抗原的表达，并使这些细胞对NK细胞介导的细胞毒性较不敏感。在存在HEp 2-IkappaB（（S32 AS 36 A））细胞的情况下，NK细胞分泌IFN-γ和粒细胞巨噬细胞集落刺激因子（GM-CSF）也显著增加，并且在将这些肿瘤细胞加入NK细胞培养物之前用IFN-γ处理这些肿瘤细胞减少了NK细胞释放的IFN-γ和GM-CSF。然而，当与单独载体转染的HEp 2细胞相比时，在未处理和IFN-γ处理的HEp 2-IkappaB（（S32 AS 36 A））细胞存在下，NK细胞介导的细胞毒性和IFN-γ分泌的水平保持显著更高。因此，NF κ B反向调节ICAM-1和MHC I类抗原在HEp 2肿瘤细胞上的表达，这可能有助于这些细胞对NK细胞介导的细胞毒性的抗性。
The aim of this study is to investigate the mechanisms by which elevated nuclear factor kappaB (NFkappaB) activity in HEp2 cells can modulate the function and survival of immune effector cells. Inhibition of NFkappaB functional activity by stable expression of IkappaB super-repressor rendered HEp2 cells (HEp2-IkappaB((S32AS36A))) Susceptible to natural killer (NK) cell mediated cytotoxicity. Increase in surface ICAM1 expression was greater on HEp2-IkappaB((S32AS36A)) cells than on the surface of vector alone transfected HEp2 cells when these cells were treated with IFN-gamma. In contrast, tumor necrosis factor alpha (TNF-alpha) treatment augmented ICAM-1 expression on the surface of vector-alone transfected HEp2 cells and not on the HEp2-IkappaB((S32AS36A)) cells. Moreover, synergistic augmentation of ICAM-1 by a combination of TNF-alpha and interferon-gamma (IFN-gamma) treatment was completely abrogated on the surface of HEp2-IkappaB((S32AS36A)) cells. The addition of blocking antibody to ICAM-1 surface antigen partially inhibited the increased cytotxicity mediated by interleukin-2 treated NK cells against HEp2-IkappaB((S32AS36A)) cells. In contrast to ICAM-1, the expression of major histocompatibility complex (MHC) class I antigens were down-regulated when the function of nuclear NFkappaB was inhibited in HEp2 cells. The addition of IFN-gamma to HEp2-kappaB((S32AS36A)) cells increased the expression of MHC class I antigen and rendered these cells less susceptible to NK cell mediated cytotoxicity. Secretion of IFN-gamma and granulocyte macrophage-colony-stimulating factor (GM-CSF) by NK cells was also significantly increased in the presence of HEp2-IkappaB((S32AS36A)) cells, and the treatment of these tumor cells with IFN-gamma prior to their addition to the cultures of NK cells decreased the released IFN-gamma and GM-CSF by NK cells. However, the levels of NK cell mediated cytotoxicity and IFN-gamma secretion remained significantly higher in the presence of both untreated and IFN-gamma treated HEp2-IkappaB((S32AS36A)) cells when compared with vector-alone transfected HEp2 cells. Thus, NFkappaB regulates inversely the expression of ICAM-1 and MHC class I antigens on HEp2 tumor cells and this may contribute to the resistance of these cells to NK cell mediated cytotoxicity.