The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1998/9/1039/ $5.00
The Journal of Experimental Medicine, Volume 188, Number 6, September 21, 1998 1039-1046

Articles

Inhibition of Angiogenesis by Interleukin 4

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

From the * Department of Microbiology-Immunology and {ddagger} 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 of angiogenesis. When incorporated at concentrations of 10 ng/ml or more into pellets implanted into the rat cornea or when delivered systemically to the mouse by intraperitoneal injection, IL-4 blocked the induction of corneal neovascularization by basic fibroblast growth factor. IL-4 as well as IL-13 inhibited the migration of cultured bovine or human microvascular cells, showing unusual dose–response curves that were sharply stimulatory at a concentration of 0.01 ng/ml but inhibitory over a wide range of higher concentrations. Recombinant cytokine from mouse and from human worked equally well in vitro on bovine and human endothelial cells and in vivo in the rat, showing no species specificity. IL-4 was secreted at inhibitory levels by activated murine T helper (TH0) cells and by a line of carcinoma cells whose tumorigenicity is known to be inhibited by IL-4. Its ability to cause media conditioned by these cells to be antiangiogenic suggested that the antiangiogenic activity of IL-4 may play a role in normal physiology and contribute significantly to its demonstrated antitumor activity.

Key Words: neovascularization • tumor angiogenesis • endothelial cell • migration • cornea assay

Address correspondence to Noël Bouck, R.H. Lurie Cancer Center, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, IL 60611. Phone: 312-503-5934; Fax: 312-908-1372; E-mail: n-bouck{at}nwu.edu

It is a pleasure to thank Bob Coffman of DNAX for crucial advice on in vivo dosing with IL-4 and the Schering Plough Research Institute for supplying the cytokine used for the in vivo work.

We also thank the National Institutes of Health for the grants that supported this work: CA52750 and CA64239 (N.P. Bouck), AR30692 and AR41492 (A.E. Koch) and AA08275 (C. Waltenbaugh). AEK also receives funds from the Veterans Administration Research Service, the Arthritis Foundation Illinois Chapter Wolkonsky Award for Rheumatoid Arthritis Research Grant and the Gallagher Professorship for Arthritis Research.

Abbreviations used: bFGF, basic fibroblast growth factor; FBS, fetal bovine serum; HMVEC, human dermal microvascular endothelial cells; hu, human recombinant; mu, murine recombinant; VCAM-1, vascular cell adhesion molecule 1.


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