Kelly G D, Ensoli B, Gunthel C J, Offermann M K
Winship Cancer Center, Department of Medicine, Emory University, Atlanta, Georgia 30322, USA.
AIDS. 1998 Oct 1;12(14):1753-61. doi: 10.1097/00002030-199814000-00006.
Kaposi's sarcoma (KS) is a neoplasm strongly associated with HIV-1 infection and marked by leukocytic infiltration. The infiltrating leukocytes are a possible source of inflammatory cytokines, human herpesvirus 8 (HHV8) and the HIV-1 transactivator protein Tat. This study examines whether Tat directly induces expression of cellular adhesion molecules and cytokines in KS cells and whether this induction differs in kinetics and magnitude from induction by tumour necrosis factor (TNF) alpha.
Changes in gene expression in response to recombinant Tat compared with those to TNFalpha were evaluated at the messenger (m) RNA and protein level using cells that were cultured from KS lesions.
Tat induced the expression of the adhesion molecules vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) and the cytokines monocyte chemoattractant protein 1 (MCP-1) and interleukin 6 (IL-6). The inductions were observed at both the protein and mRNA levels. The pattern of mRNA induction over time in response to Tat differed from that to TNFalpha, with higher peak levels that occurred earlier in response to Tat. The expression of these genes is, in part, regulated by the transcription factor NF-kappaB. Tat and TNFalpha activated comparable levels of NF-kappaB.
The ability of the HIV-1 Tat to induce the expression of genes with kinetics that are distinct from those seen in TNFalpha induction suggests that mechanisms in addition to activation of NF-kappaB contribute to the observed induction. Tat may contribute to the pathogenesis of AIDS-related KS through induction of cellular genes that are pro-proliferative and proinflammatory and may enhance the recruitment of leukocytes, which are a possible source of further cytokines, Tat and HHV8.
卡波西肉瘤（KS）是一种与人类免疫缺陷病毒1型（HIV-1）感染密切相关的肿瘤，其特征为白细胞浸润。浸润的白细胞可能是炎性细胞因子、人类疱疹病毒8型（HHV8）和HIV-1反式激活蛋白Tat的来源。本研究旨在探讨Tat是否直接诱导KS细胞中细胞黏附分子和细胞因子的表达，以及这种诱导在动力学和强度上是否与肿瘤坏死因子（TNF）α的诱导不同。
使用从KS病变培养的细胞，在信使（m）RNA和蛋白质水平评估与TNFα相比，重组Tat诱导的基因表达变化。
Tat诱导黏附分子血管细胞黏附分子1（VCAM-1）和细胞间黏附分子1（ICAM-1）以及细胞因子单核细胞趋化蛋白1（MCP-1）和白细胞介素6（IL-6）的表达。在蛋白质和mRNA水平均观察到诱导作用。Tat诱导的mRNA随时间变化的模式与TNFα不同，Tat诱导的峰值水平更高且出现更早。这些基因的表达部分受转录因子NF-κB调控。Tat和TNFα激活的NF-κB水平相当。
HIV-1 Tat诱导基因表达的动力学与TNFα诱导不同，这表明除了NF-κB激活之外的机制也有助于观察到的诱导作用。Tat可能通过诱导促增殖和促炎的细胞基因，促进与艾滋病相关的KS发病机制，并可能增强白细胞的募集，而白细胞可能是进一步的细胞因子、Tat和HHV8的来源。
