PURIFIED TAT INDUCES INFLAMMATORY RESPONSE GENES IN KAPOSIS-SARCOMA CELLS

Objective: Kaposi's sarcoma (KS) is a neoplasm strongly associated wit h HIV-1 infection and marked by leukocytic infiltration. The infiltrat ing leukocytes are a possible source of inflammatory cytokines, human herpesvirus 8 (HHV8) and the HIV-1 transactivator protein Tat. This st udy examines whether Tat directly induces expression of cellular adhes ion molecules and cytokines in KS cells and whether this induction dif fers in kinetics and magnitude from induction by tumour necrosis facto r (TNF) alpha. Design and method: Changes in gene expression in respon se to recombinant Tat compared with those to TNF alpha were evaluated at the messenger (m) RNA and protein level using cells that were cultu red from KS lesions. Results: Tat induced the expression of the adhesi on molecules vascular cell adhesion molecule 1 (VCAM-1) and intercellu lar adhesion molecule 1 (ICAM-1) and the cytokines monocyte chemoattra ctant protein 1 (MCP:1) and interleukin 6 (IL-6). The inductions were observed at both the protein and mRNA levels. The pattern of mRNA indu ction over time in response to Tat differed from that to TNF alpha, wi th higher peak levels that occurred earlier in response to Tat. The ex pression of these genes is, in part, regulated by the transcription fa ctor NF-kappa B. Tat and TNF alpha activated comparable levels of NF-k appa B. Conclusions: The ability of the HIV-1 Tat to induce the expres sion of genes with kinetics that are distinct from those seen in TNF a lpha induction suggests that mechanisms in addition to activation of N F-kappa B contribute to the observed induction. Tat may contribute to the pathogenesis of AIDS-related KS through induction of cellular gene s that are pro-proliferative and proinflammatory and may enhance the r ecruitment of leukocytes, which are a possible source of further cytok ines, Tat and HHV8. (C) 1998 Lippincott Williams & Wilkins.