INFLAMMATORY CYTOKINES INDUCE ENDOTHELIAL-CELLS TO PRODUCE AND RELEASE BASIC FIBROBLAST GROWTH-FACTOR AND TO PROMOTE KAPOSIS SARCOMA-LIKE LESIONS IN NUDE-MICE

Inflammatory cytokines including TNF-alpha, IL-1 beta, and IFN-gamma a re increased in sera and lesions of Kaposi's sarcoma (KS) patients. Pr evious data have indicated that the combination of these cytokines as found in conditioned media from activated T cells induces normal endot helial cells to acquire the features of KS spindle cells (KS cells) in cluding spindle morphology, marker expression, and the responsiveness to the effects of HIV-1 Tat protein. Conditioned media from activated T cells or the single cytokines also induce AIDS-KS cells to produce a nd release basic fibroblast growth factor (bFCF). bFCF is highly expre ssed also by in situ KS cells and mediates KS-like lesion formation af ter inoculation of the cells in nude mice. Here we show that both larg e and small vessel endothelial cells chronically exposed to inflammato ry cytokines produce and release bioactive bFGF in the absence of cell death. In addition, after this treatment, endothelial cells acquire a ngiogenic capability and induce KS-like lesions after inoculation in n ude mice. Production and release of bFCF is induced in a synergistic f ashion by TNF-alpha, IL-1 beta, and IFN-gamma, and its release is furt her promoted by low cell density and by the serine proteases plasmin a nd thrombin. These results indicate that inflammatory cytokines induce endothelial cells to export bFGF and to acquire angiogenic properties , a key feature of the KS cell phenotype, and suggest a mechanism by w hich these cytokines can cooperate in the induction of KS.