HLA CLASS-I HEAVY-CHAIN GENE PROMOTER ELEMENTS MEDIATING SYNERGY BETWEEN TUMOR-NECROSIS-FACTOR AND INTERFERONS
HLA CLASS-I HEAVY-CHAIN GENE PROMOTER ELEMENTS MEDIATING SYNERGY BETWEEN TUMOR-NECROSIS-FACTOR AND INTERFERONS
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DOI：
10.1128/mcb.14.2.1322
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发表时间：
1994-02-01
影响因子：
5.3
通讯作者：
POBER, JS
中科院分区：
文献类型：
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作者：
JOHNSON, DR;POBER, JS
细胞因子肿瘤坏死因子（TNF）、β干扰素（IFN-β）和IFN-γ增加主要组织相容性复合物I类分子表达。大于加性（即，在用TNF与任一类型的IFN组合处理的HeLa细胞中观察到I类重链mRNA的协同）诱导。为了确定介导细胞因子协同作用的顺式作用元件，将人主要组织相容性复合体I类重链基因（HLA-B7）的启动子置于报告基因的前面并转染到HeLa细胞中。缺失分析将协同作用所需的元件映射到包含kappa B样元件和干扰素共有序列（ICS）的40-bp区域，该元件是对TNF的反应所必需的，该序列是对IFN的反应所必需的。当这些元件的方向被颠倒或它们正常的20-bp间距减少5或10 bp时，即，DNA螺旋的半圈或一整圈，获得基本上相等的响应，表明这些参数不是关键的。在电迁移率变动测定中，来自TNF处理的细胞的含有p50的NF-κ B核因子结合含有κ B的探针，并且来自IFN-γ处理的细胞的ISGF-2结合含有ICS的探针。含有kappa B和ICS元件的探针（kappa B-ICS）与从TNF和IFN-γ处理的细胞中分离的核因子形成新的复合物;当在体外混合来自单独的精氨酸处理的细胞的核因子时，也形成该复合物。在HLA-A中发现的天然变体ICS响应IFN-γ，并可介导与TNF的协同作用。然而，在HLA-C中发现的变体κ B对TNF不应答，也不能介导TNF和IFN-γ之间的协同作用。这些观察结果表明，TNF和IFN之间的协同作用，在诱导HLA I类基因表达的结果从总的个人相互作用的精氨酸激活的增强子结合因子与转录起始复合物。
The cytokines tumor necrosis factor (TNF), beta interferon (IFN-beta), and IFN-gamma increase major histocompatibility complex class I molecule expression. A greater than additive (i.e., synergistic) induction of class I heavy-chain mRNA is observed in HeLa cells treated with TNF in combination with either type of IFN. To define the cis-acting elements mediating cytokine synergy, the promoter of a human major histocompatibility complex class I heavy-chain gene (HLA-B7) was placed in front of a reporter gene and transfected into HeLa cells. Deletion analysis mapped the elements required for synergy to a 40-bp region containing a kappa B-like element, which is necessary for the response to TNF, and an interferon consensus sequence (ICS), which is necessary for the responses to IFNs. When the orientation of these elements was reversed or their normal 20-bp spacing was reduced by 5 or 10 bp, i.e., one half or one full turn of the DNA helix, essentially equivalent responses were obtained, suggesting that these parameters are not critical. In electromobility shift assays, a p50-containing NF-kappa B nuclear factor from TNF-treated cells binds kappa B-containing probes, and ISGF-2 from IFN-gamma-treated cells binds ICS-containing probes. A probe containing both the kappa B and ICS elements (kappa B-ICS) forms a novel complex with nuclear factors isolated from cells treated with both TNF and IFN-gamma; this complex also forms when nuclear factors from individually cytokine-treated cells are mixed in vitro. The natural variant ICS found in HLA-A responds to IFN-gamma and can mediate synergy with TNF. However, the variant kappa B found in HLA-C does not respond to TNF, nor can it mediate synergy between TNF and IFN-gamma. These observations suggest that synergy between TNF and IFNs in the induction of HLa class I gene expression results from the sum of individual interactions of cytokine-activated enhancer-binding factors with the transcription initiation complex.