Qin J Z, Bacon P, Chaturvedi V, Nickoloff B J
Department of Pathology, Skin Cancer Research Program, Loyola University Medical Center, Loyola University of Chicago, Chicago, Illinois, USA.
J Invest Dermatol. 2001 Oct;117(4):898-907. doi: 10.1046/j.0022-202x.2001.01477.x.
An important step in tumorigenesis involves loss of sensitivity to various apoptotic signals by malignant cells, imbuing them with an enhanced survival phenotype. NF-kappaB also regulates epidermal thickness, susceptibility to apoptosis, and tumor formation in skin. Keratinocytes were examined for their susceptibility to apoptosis using cytokines produced during an immunologic response to tumor antigens, i.e., interferon-gamma and/or tumor necrosis factor-alpha (TNF-alpha). The role for NF-kappaB in this response was examined using a retroviral vector containing a degradation-resistant form of IkappaBalpha. Whereas interferon-gamma and TNF-alpha either alone or in combination did not induce apoptosis in keratinocytes, after infection with the retrovirus to block NF-kappaB activation they became susceptible to TNF-alpha but not Fas-induced apoptosis. Moreover, when keratinocytes with repressed NF-kappaB activity were simultaneously treated with interferon-gamma, there was a synergistic induction of apoptosis by TNF-alpha that was dependent on FADD, tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL), and caspase activation. Molecular abnormalities accompanying repressed NF-kappaB activity included failure to induce TNF-RII receptor together with enhanced levels of TRAIL death receptor 4. The ability of interferon-gamma when combined with TNF-alpha to mediate keratinocyte apoptosis included induction of TRAIL coupled with diminished capacity of keratinocytes with repressed NF-kappaB activity to increase the TRAIL decoy receptor-1, as well as lower levels of several NF-kappaB-dependent antiapoptotic proteins accompanied by enhanced caspase 8 levels. These results indicate that interferon-gamma and TNF-alpha synergistically induce keratinocyte apoptosis when concomitant induction of NF-kappaB is blocked. Participants in the apoptotic response mediated by NF-kappaB, besides cell-survival proteins, include modulation of TRAIL and both death and decoy receptors. Thus, not only does NF-kappaB signaling influence the intrinsic survival pathway for keratinocytes in normal skin, but it may also play a role in determining the apoptotic response to cytokines generated during an immune response via TRAIL produced by the keratinocytes themselves.
肿瘤发生过程中的一个重要步骤涉及恶性细胞对各种凋亡信号的敏感性丧失，赋予它们增强的生存表型。核因子-κB（NF-κB）还调节表皮厚度、对凋亡的易感性以及皮肤中的肿瘤形成。使用在对肿瘤抗原的免疫反应过程中产生的细胞因子，即干扰素-γ和/或肿瘤坏死因子-α（TNF-α），检测角质形成细胞对凋亡的易感性。使用含有抗降解形式的IκBα的逆转录病毒载体研究NF-κB在该反应中的作用。虽然干扰素-γ和TNF-α单独或联合使用均未诱导角质形成细胞凋亡，但在用逆转录病毒感染以阻断NF-κB激活后，它们变得对TNF-α敏感，但对Fas诱导的凋亡不敏感。此外，当NF-κB活性受到抑制的角质形成细胞同时用干扰素-γ处理时，TNF-α会协同诱导凋亡，这依赖于FADD、肿瘤坏死因子相关凋亡诱导配体（TRAIL）和半胱天冬酶激活。伴随NF-κB活性受抑制的分子异常包括未能诱导TNF-RII受体以及TRAIL死亡受体4水平升高。干扰素-γ与TNF-α联合介导角质形成细胞凋亡的能力包括诱导TRAIL，同时NF-κB活性受抑制的角质形成细胞增加TRAIL诱饵受体-1的能力降低，以及几种NF-κB依赖性抗凋亡蛋白水平降低，同时半胱天冬酶8水平升高。这些结果表明，当NF-κB的伴随诱导被阻断时，干扰素-γ和TNF-α协同诱导角质形成细胞凋亡。除细胞存活蛋白外，NF-κB介导的凋亡反应参与者还包括TRAIL以及死亡受体和诱饵受体的调节。因此，NF-κB信号传导不仅影响正常皮肤中角质形成细胞的内在生存途径，而且可能在决定对免疫反应过程中由角质形成细胞自身产生的TRAIL所产生的细胞因子的凋亡反应中起作用。
