INHIBITION OF ANGIOGENESIS BY INTERLEUKIN-4

Interleukin (IL)-4, a crucial modulator of the immune system and an ac tive antitumor agent, is also a potent inhibitor of angiogenesis. When incorporated at concentrations of 10 ng/ml or more into pellets impla nted into the rat cornea or when delivered systemically to the mouse b y intraperitoneal injection, IL-4 blocked the induction of corneal neo vascularization by basic fibroblast growth factor. IL-4 as well as IL- 13 inhibited the migration of cultured bovine or human microvascular c ells, showing unusual dose-response curves that were sharply stimulato ry at a concentration of 0.01 ng/ml but inhibitory over a wide range o f higher concentrations. Recombinant cytokine from mouse and from huma n worked equally well in vitro on bovine and human endothelial cells a nd in vivo in the rat, showing no species specificity. IL-4 was secret ed at inhibitory levels by activated murine T helper (THO) cells and b y a line of carcinoma cells whose tumorigenicity is known to be inhibi ted by IL-4. Its ability to cause media conditioned by these cells to be antiangogenic suggested that the antiangiogenic activity of IL-4 ma y play a role in normal physiology and contribute significantly to its demonstrated antitumor activity.