Inhibition of Angiogenesis by Interleukin 4

doi:10.1084/jem.188.6.1039

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J. Exp. Med., Volume 188, Number 6, September 21, 1998 1039-1046

Inhibition of Angiogenesis by Interleukin 4

By Olga V. Volpert,^* Tim Fong, Alisa E. Koch, Jeffrey D. Peterson,^* Carl Waltenbaugh,^* Robert I. Tepper,^§ and Noël P. Bouck^*

From the ^* Department of Microbiology-Immunology and Department of Medicine and R.H. Lurie Cancer Center, Northwestern University Medical School, Chicago, Illinois 60611; and ^§ Millennium Pharmaceuticals Incorporated, Cambridge, Massachusetts 02139

Interleukin (IL)-4, a crucial modulator of the immune system and an active antitumor agent, is also a potent inhibitor ofangiogenesis. When incorporated at concentrations of 10 ng/mlor more into pellets implanted into the rat cornea or when deliveredsystemically to the mouse by intraperitoneal injection, IL-4 blockedthe induction of corneal neovascularization by basic fibroblastgrowth factor. IL-4 as well as IL-13 inhibited the migration ofcultured bovine or human microvascular cells, showing unusualdose-response curves that were sharply stimulatory at a concentrationof 0.01 ng/ml but inhibitory over a wide range of higher concentrations.Recombinant cytokine from mouse and from human worked equallywell in vitro on bovine and human endothelial cells and in vivoin the rat, showing no species specificity. IL-4 was secretedat inhibitory levels by activated murine T helper (T_H0) cellsand by a line of carcinoma cells whose tumorigenicity is knownto be inhibited by IL-4. Its ability to cause media conditionedby these cells to be antiangiogenic suggested that the antiangiogenicactivity of IL-4 may play a role in normal physiology and contributesignificantly to its demonstrated antitumor activity.

Key words: neovascularization; tumor angiogenesis; endothelial cell; migration; cornea assay

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