ACTIVATION OF MONOCYTES BY HIV-TAT TREATMENT IS MEDIATED BY CYTOKINE EXPRESSION

Treatment of primary monocytes with soluble HIV-Tat protein is associa ted with increased monocyte metalloproteinase-9 (MMP-9) expression and enhanced beta(2) integrin expression that increases monocyte/endothel ial adhesion. These alterations require greater than 12 h of HIV-Tat t reatment, suggesting the involvement of intermediate factors. Thus, we have examined the role of cytokines in the HIV-Tat-induced alteration of monocyte function. Treatment of monocytes with HIV-Tat rapidly upr egulated the production of IL-1 beta, IL-6, IL-8, and TNF-alpha, but n ot IL-3, granulocyte-macrophage CSF, basic fibroblast growth factor, o r macrophage-inflammatory protein-1 alpha, and was associated with up- regulation of the corresponding cytokine mRNA. Inclusion of neutralizi ng anti-cytokine Abs to IL-1 beta or TNF-alpha during the HIV-Tat pret reatment period significantly inhibited the HIV-Tat-induced increase i n MMP-9 production, monocyte/endothelial adhesion, and monocyte-depend ent endothelial damage. In contrast, neutralizing Abs against IL-6 and IL-8 had no effect. The effects of HIV-Tat treatment, namely MMP-9 pr oduction, enhanced monocyte/endothelial cell adhesion, and monocyte-de pendent endothelial damage, were mimicked by treating the monocytes wi th IL-1 beta or TNF-alpha, but not with IL-6 or IL-8. Therefore, the m echanism by which HIV-Tat activates monocyte function is dependent on HIV-Tat-induced production of cytokines (IL-1 beta and TNF-alpha).