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.
Saleh
M
M
Neuroscience Centre, Department of Surgery and Neurosurgery, The University of Melbourne, Victoria, Australia. Saleh@licre.Ludwig.edu.au
Davis
I D
ID
Wilks
A F
AF
D000818:Animals; D001932:Brain Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism*; D002455:Cell Division / Q000502:physiology; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000235:genetics / Q000378:metabolism; D016228:Endothelial Growth Factors / Q000096:biosynthesis; D004727:Endothelium / Q000378:metabolism / Q000502:physiology; D004804:Eosinophils / Q000166:cytology; D005260:Female; D005822:Genetic Vectors; D005910:Glioma / Q000098:blood supply / Q000235:genetics / Q000378:metabolism*; D015847:Interleukin-4 / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D008222:Lymphokines / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009336:Necrosis; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis; D017978:Receptors, Growth Factor / Q000096:biosynthesis; D040262:Receptors, Vascular Endothelial Growth Factor; D013752:Tetracycline / Q000378:metabolism / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D018076:DNA, Complementary; D016228:Endothelial Growth Factors; D008222:Lymphokines; D017978:Receptors, Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D015847:Interleukin-4; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D013752:Tetracycline