Purified Tat induces inflammatory response genes in Kaposi's sarcoma cells


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Abstract

Objective: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) α.Design and method:Changes in gene expression in response to recombinant Tat compared with those to TNFα were evaluated at the messenger (m) RNA and protein level using cells that were cultured from KS lesions.Results: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 TNFα, 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-κB. Tat and TNFα activated comparable levels of NF-κB.Conclusions:The ability of the HIV-1 Tat to induce the expression of genes with kinetics that are distinct from those seen in TNFα induction suggests that mechanisms in addition to activation of NF-κB 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.

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