Effects of Tenofovir on Cytokines and Nucleotidases in HIV-1 Target Cells and the Mucosal Tissue Environment in the Female Reproductive Tract
Effects of Tenofovir on Cytokines and Nucleotidases in HIV-1 Target Cells and the Mucosal Tissue Environment in the Female Reproductive Tract
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DOI：
10.1128/aac.03270-14
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发表时间：
2014-11-01
影响因子：
4.9
通讯作者：
Wira, Charles R.
中科院分区：
文献类型：
--
作者：
Biswas, Nabanita;Rodriguez-Garcia, Marta;Wira, Charles R.
替诺福韦（TFV）是一种逆转录酶抑制剂，用于预防HIV感染的杀微生物剂暴露前预防试验。认识到细胞因子/趋化因子分泌和核苷酸酶生物活性的变化可以影响女性生殖道（FRT）对HIV感染的免疫保护，我们测试了TFV调节FRT免疫保护的假设。从子宫切除术后的子宫内膜（Em）、宫颈内膜（Cx）和宫颈外膜（Ecx）中分离上皮细胞、成纤维细胞、CD 4（+）T细胞和CD 14（+）细胞。在存在或不存在TFV的情况下，分析了促炎细胞因子（巨噬细胞炎症蛋白3 α [MIP-3 α]、白细胞介素8 [IL-8]和肿瘤坏死因子α [TNF-alpha]）的水平、特定核苷酸酶的表达水平和核苷酸酶生物活性。TFV以细胞和位点特异性方式影响mRNA和/或蛋白质细胞因子和核苷酸酶。TFV显著增强Em和Ecx上皮细胞的IL-8和TNF-α分泌，但不增强Cx上皮细胞的分泌。与此相反，在响应TFV，IL-8分泌显着减少Em和Cx成纤维细胞，但增加与成纤维细胞从Ecx。当与来自FRT的CD 4（+）T细胞孵育时，TFV增加IL-8（Em和Ecx）和TNF-α（Cx和Ecx）分泌水平。此外，当与Em CD 14（+）细胞孵育时，相对于对照组，TFV显着增加了MIP-3 α、IL-8和TNF-alpha的分泌水平。相反，TFV显著降低上皮细胞（Cx）和CD 4（+）T细胞（Em）中的核苷酸酶生物活性，但增加成纤维细胞（Em）中的核苷酸酶生物活性。我们的研究结果表明，TFV调节FRT内不同部位的上皮细胞、成纤维细胞、CD 4（+）T细胞和CD 14（+）细胞中的促炎细胞因子、核苷酸酶基因表达和核苷酸酶生物活性。
Tenofovir (TFV) is a reverse transcriptase inhibitor used in microbicide preexposure prophylaxis trials to prevent HIV infection. Recognizing that changes in cytokine/chemokine secretion and nucleotidase biological activity can influence female reproductive tract (FRT) immune protection against HIV infection, we tested the hypothesis that TFV regulates immune protection in the FRT. Epithelial cells, fibroblasts, CD4(+) T cells, and CD14(+) cells were isolated from the endometrium (Em), endocervix (Cx), and ectocervix (Ecx) following hysterectomy. The levels of proinflammatory cytokines (macrophage inflammatory protein 3 alpha [MIP-3 alpha], interleukin 8 [IL-8], and tumor necrosis factor alpha [TNF-alpha]), the expression levels of specific nucleotidases, and nucleotidase biological activities were analyzed in the presence or absence of TFV. TFV influenced mRNA and/or protein cytokines and nucleotidases in a cell-and site-specific manner. TFV significantly enhanced IL-8 and TNF-alpha secretion by epithelial cells from the Em and Ecx but not from the Cx. In contrast, in response to TFV, IL-8 secretion was significantly decreased in Em and Cx fibroblasts but increased with fibroblasts from the Ecx. When incubated with CD4(+) T cells from the FRT, TFV increased IL-8 (Em and Ecx) and TNF-alpha (Cx and Ecx) secretion levels. Moreover, when incubated with Em CD14(+) cells, TFV significantly increased MIP-3 alpha, IL-8, and TNF-alpha secretion levels relative to those of the controls. In contrast, nucleotidase biological activities were significantly decreased by TFV in epithelial (Cx) and CD4(+) T cells (Em) but increased in fibroblasts (Em). Our findings indicate that TFV modulates proinflammatory cytokines, nucleotidase gene expression, and nucleotidase biological activity in epithelial cells, fibroblasts, CD4(+) T cells, and CD14(+) cells at distinct sites within the FRT.