Mori N, Ueda A, Ikeda S, Yamasaki Y, Yamada Y, Tomonaga M, Morikawa S, Geleziunas R, Yoshimura T, Yamamoto N
Department of Preventive Medicine and AIDS Research, Institute of Tropical Medicine, Nagasaki University, Japan.
Cancer Res. 2000 Sep 1;60(17):4939-45.
Infection by human T-cell leukemia virus type (HTLV) I leads to adult T-cell leukemia and is also associated with the neurodegenerative disease HTLV-I-associated myelopathy/tropical spastic paraparesis. Leukocytes are attracted to sites of inflammation by chemokines. One such chemokine is monocyte chemoattractant protein (MCP)-1, a member of the C-C subfamily of chemokines. We investigated whether HTLV-I infection causes up-regulation of MCP-1, which may in turn cause recruitment of leukocytes to HTLV-I-infected areas. We now report that MCP-1 mRNA levels are elevated in HTLV-I-infected T-cell lines, when compared with uninfected ones. We further confirmed secretion of MCP-1 by HTLV-I-infected T-cell lines. MCP-1 mRNA was also expressed in leukemic cells from patients with adult T-cell leukemia. The 5' transcriptional regulatory region of the MCP-1 gene was activated by the HTLV-I-encoded transactivator Tax in the human T-cell line Jurkat, in which endogenous MCP-1 is induced by Tax. By using site-specific point mutations, we have identified two closely spaced nuclear factor (NF)-kappaB sites, A1 and A2, to be important for Tax-mediated transactivation of the MCP-1 gene. Through the use of an electrophoretic mobility shift assay, we demonstrated that Tax induced NF-kappaB binding to both MCP-1 kappaB sites. This is the first report to demonstrate that Tax can transactivate the MCP-1 gene through the induction of NF-kappaB. Our results thus reveal how Tax disrupts the normally regulated MCP-1 gene and leads to its constitutive expression in HTLV-I-infected cells. These findings may have important implications for our understanding of HTLV-I-associated diseases.
人类T细胞白血病病毒I型(HTLV-I)感染可导致成人T细胞白血病,还与神经退行性疾病HTLV-I相关脊髓病/热带痉挛性截瘫有关。趋化因子可将白细胞吸引至炎症部位。单核细胞趋化蛋白(MCP)-1就是这样一种趋化因子,它是趋化因子C-C亚家族的成员。我们研究了HTLV-I感染是否会导致MCP-1上调,而MCP-1上调反过来可能会导致白细胞募集至HTLV-I感染区域。我们现在报告,与未感染的T细胞系相比,HTLV-I感染的T细胞系中MCP-1 mRNA水平升高。我们进一步证实了HTLV-I感染的T细胞系分泌MCP-1。MCP-1 mRNA也在成人T细胞白血病患者的白血病细胞中表达。在人T细胞系Jurkat中,HTLV-I编码的反式激活因子Tax激活了MCP-1基因的5'转录调控区域,在该细胞系中内源性MCP-1可被Tax诱导。通过使用位点特异性点突变,我们确定了两个紧密相邻的核因子(NF)-κB位点A1和A2,它们对于Tax介导的MCP-1基因反式激活很重要。通过使用电泳迁移率变动分析,我们证明Tax诱导NF-κB与两个MCP-1 κB位点结合。这是第一份证明Tax可通过诱导NF-κB反式激活MCP-1基因的报告。因此,我们的结果揭示了Tax如何破坏正常调控的MCP-1基因并导致其在HTLV-I感染细胞中组成性表达。这些发现可能对我们理解HTLV-I相关疾病具有重要意义。