Inhibition of Angiogenesis by Interleukin 4

Abstract

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.

Paradoxical Roles of IL-4 in Tumor Immunity

“…Basic fibroblast growth factor (bFGF) is a potent inducer of angiogenesis and mounted a vigorous angiogenic response when implanted into the avascular cornea of rats as hydron pellet (25). However, the angiogenesis was completely blocked by IL-4.…”

“…However, the angiogenesis was completely blocked by IL-4. When anti-IL-4 mAb was added, new blood vessels formed again (25). In vitro, IL-4 inhibited the migration of cultured bovine and human microvascular cells and suppressed the formation of tube-like structure by human umbilical vein endothelial cells (HUVEC) induced by vascular endothelial growth factor (VEGF) and bFGF (26).…”

“…Maybe the different expression patterns, including dose and time, result in the different effects. Actually, opposite effects of low and high dose IL-4 had been demonstrated by Volpert (25). They studied the migration of bovine adrenal capillary endothelial cells and human dermal capillary endothelial cells in the presence of a wide range (10 -3 -10 2 ng/ml) IL-4.…”

“…They studied the migration of bovine adrenal capillary endothelial cells and human dermal capillary endothelial cells in the presence of a wide range (10 -3 -10 2 ng/ml) IL-4. The effects of IL-4 exhibited a biphasic modality with low concentration (10 -3 -10 -2 ng/ml) promoting and high concentration (10 -1 -10 2 ng/ml) inhibiting endothelial cell migration (25). Recently, our group is studying the time and dose effects of IL-4 expression on tumor growth.…”

Retrovirus-mediated IL-4 gene therapy in spontaneous adenocarcinomas from MMTV-neu transgenic mice

“…13 As no eosinophils were seen in non-injected contralateral tumors in IL-4 treated mice, it is likely that other cellular components of the immune response were instrumental in mediating the partial systemic effect detected in our model. In addition, IL-4 has recently been proposed to have an anti-angiogenic effect, 24 although this activity was not evaluated in our study.…”