Transactivation of the interleukin-1 alpha promoter by human T-cell leukemia virus type I and type II tax proteins
Transactivation of the interleukin-1 alpha promoter by human T-cell leukemia virus type I and type II tax proteins
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DOI：
10.1182/blood.v87.8.3410.bloodjournal8783410
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发表时间：
1996-04-15
期刊：
影响因子：
20.3
通讯作者：
Prager, D
中科院分区：
文献类型：
--
作者：
Mori, N;Prager, D
人T细胞白血病病毒I型（HTLV-I）感染的T细胞系组成性地产生高水平的白细胞介素-1 α（IL-1 α）。为了分析导致IL-1 α在HTLV-I感染的细胞系中表达的机制，我们研究了参与IL-1 α基因活化的人IL-1 α启动子的调节区。IL-1 α启动子构建体驱动氯霉素乙酰转移酶（CAT）报告基因在HTLV-I阳性MT-2细胞中的转录，所述MT-2细胞组成性地产生IL-1 α。在共转染试验中，HTLV-I和HTLV-II的Tax蛋白在未感染的Jurkat细胞系中特异性激活IL-1 α启动子的转录。突变Tax蛋白缺乏核因子（NF）-κ B途径的基因反式激活，不能诱导IL-1 α启动子-CAT构建体的转录活性，但通过外源性提供p65/p50 NF-κ B来拯救。我们发现两个IL-1 α κ B样位点（位置-1，065至-1，056和+646至+655）与MT-2细胞的含NF-κ B的核提取物特异性地形成复合物，并且NF-κ B与3 'NF-κ B结合位点的亲和力高于与5' NF-κ B位点的亲和力。此外，5 '或3' NF-κ B位点的缺失降低了MT-2细胞中IL-1 α启动子的活性和Jurkat细胞中外源NF-κ B和Tax对IL-1 α启动子的反式激活。这些数据表明Tax通过NF-κ B途径诱导IL-1 α基因转录的一般作用。HTLV-I感染细胞表达IL-1 α可能在HTLV-I诱导的成人T细胞白血病/淋巴瘤患者常见的高钙血症、溶骨性骨病变、嗜中性粒细胞、C反应蛋白升高和发热中起重要作用。(C)1996年，美国血液学会。
Human T-cell leukemia virus type I (HTLV-I)-infected T-cell lines constitutively produce high levels of interleukin-1 alpha (IL-1 alpha), To analyze the mechanisms that lead to the expression of IL-1 alpha in HTLV-I-infected cell lines, we studied regulatory regions of the human IL-1 alpha promoter involved in activation of the IL-1 alpha gene. IL-1 alpha promoter constructs drive transcription of the chloramphenicol acetyltransferase (CAT) reporter gene in HTLV-I-positive MT-2 cells, which constitutively produce IL-1 alpha. In a cotransfection assay, the Tax protein of both HTLV-I and HTLV-II specifically activated transcription from the IL-1 alpha promoter in an uninfected Jurkat cell line. A mutant Tax protein deficient in transactivation of genes by the nuclear factor (NF)-kappa B pathway was unable to induce transcriptional activity of IL-1 alpha promoter-CAT constructs, but was rescued by exogenous provision of p65/p50 NF-kappa B. We found that two IL-1 alpha kappa B-like sites (positions -1,065 to -1,056 and +646 to +655) specifically formed a complex with NF-kappa B-containing nuclear extract from MT-2 cells and that NF-kappa B bound with higher affinity to the 3' NF-kappa B binding site than to the 5' NF-kappa B site. Moreover, deletion of either 5' or 3' NF-kappa B sites reduced IL-1 alpha promoter activity in MT-2 cells and transactivation of the IL-1 alpha promoter by exogenous NF-kappa B and Tax in Jurkat cells, These data suggest a general role for Tax induction of IL-1 alpha gene transcription by the NF-kappa B pathway. Expression of IL-1 alpha by HTLV-I productively infected cells may be important in the hypercalcemia, osteolytic bone lesions, neutrophilia, elevation of C-reactive protein, and fever frequently seen in patients with HTLV-I-induced adult T-cell leukemia/lymphoma. (C) 1996 by The American Society of Hematology.