Tumor necrosis factor type alpha, a potent inhibitor of endothelial cell growth in vitro, is angiogenic in vivo.

Abstract

Tumor necrosis factor type .alpha. (TNF-.alpha.) inhibits endothelial cell proliferation in vitro. Basal cell growth (in the absence of exogenously added growth factor) and fibroblast growth factor (FGF)-stimulated cell proliferation are inhibited in a dose-dependent manner from 0.1 to 10 ng/ml with half-maximal inhibition occurring at 0.5-1.0 ng of TNF-.alpha. per ml. Bovine aortic and brain capillary endothelial and smooth muscle cells are similarly affected. TNF-.alpha. is a noncompetitive antagonist of FGF-stimulated cell proliferation. Its action on endothelial cells is reversible and noncytotoxic. Surprisingly, TNF-.alpha. does not seem to inhibit endothelial cell proliferation in vivo. In the rabbit cornea, even a high dose of TNF-.alpha. (10 .mu.g) does not suppress angiogenesis induced by basic FGF. On the contrary, in this model system TNF-.alpha. stimulates neovascularization. The inflammatory response that is seen in the cornea after TNF-.alpha. implantation suggests that the angiogenic properties of this agent may be a consequence of leukocyte infiltration.