INHIBITION OF ANGIOGENESIS IN RATS BY IL-1 RECEPTOR ANTAGONIST AND SELECTED CYTOKINE ANTIBODIES

Daily administration of 50 ng recombinant human interleukin 1-alpha (I L-1 alpha), 25 ng IL-8, 50 ng tumor necrosis factor-alpha (TNF-alpha), or 100 ng basic fibroblast growth factor (bFGF) caused intense neovas cularization in a rat sponge model. These cytokine-induced neovascular responses were inhibited by coadministration of IL-1 receptor antagon ist (IL-1ra; 50 mu g), IL-8 antiserum (IL-8-AS; 1 : 1000), TNF-alpha a ntibody (TNF-AB; 500 ng), or a monoclonal antibody to bFGF (DG2; 1000 ng), respectively. These data suggest that it is possible to manipulat e the angiogenic response elicited by a defined cytokine by its recept or antagonist or neutralizing antibody. In the absence of exogenous cy tokines, the sponge-induced angiogenesis was profoundly suppressed by dexamethasone (5 mu g/day), but not modified by IL-1ra, 1L-8-AS, TNF-A B, and DG2 alone. However, the combination of these four reagents was able to inhibit the sponge-induced neovascular response almost complet ely. These findings provide direct evidence that IL-1 alpha, IL-8, TNF -alpha and/or bFGF have an intrinsic role in angiogenesis. Further wor k is necessary to characterize the profile of these cytokines during a ngiogenesis and to elucidate the nature of their interactions.