The paracrine role of tumour-derived mIL-4 on tumour-associated endothelium.

Interleukin-4 (IL-4) has been demonstrated to possess anti-tumourigenic properties in vivo which is initially attributed to the infiltration of eosinophils proposed to occur by IL-4 binding to its receptors on endothelial cells, thereby mediating eosinophil adhesion. We have investigated whether the binding of IL-4 to receptors on endothelial cells could elicit other biological responses which may also play a role in tumour inhibition, such as angiogenesis. We have demonstrated that mouse IL-4 (mIL-4) down-regulates the expression of one of the receptors for VEGF, VEGF-R2, on endothelial cells in vitro. By generating stable transfectants of C6 glioma cells that express mIL-4 under a tetracycline-responsive promoter system, we were able to apply tight regulatory control of mIL-4 expression in vivo. Subcutaneous implantation of mIL-4/C6 cell lines in nu/nu mice revealed that tumour growth is inhibited by mIL-4 expression. mIL-4-expressing tumours were demonstrated to have a reduced level of vascularisation compared with controls, in addition to a high degree of eosinophil infiltration. Our results suggest that mIL-4 has bimodal biological roles in potentiating tumour inhibition in athymic mice: the suppression of angiogenesis and the augmentation of the host local immune response.