IL-6 is an in vitro and in vivo autocrine growth factor for middle T antigen-transformed endothelial cells.
Murine endothelial cells immortalized with the middle-size Ag of polyomavirus (PmT) cause vascular tumors in syngenic mice by recruitment of host normal endothelial cells. This pathogenic process is similar to that occurring in Kaposi's sarcoma, in which the core of the lesion is constituted by "spindle cells," which recruit normal vascular mesenchymal cells. In murine endothelial cells, PmT induces modification of the expression of genes, including that of IL-6. Since IL-6 is a pleiotrophic cytokine that also regulates endothelial cell functions related to angiogenesis, we studied the relevance of IL-6 in the tumorigenicity of PmT-endothelial cells. In vitro studies demonstrated that the spontaneous PmT-endothelial cell proliferation rate was slow during the first 6 days of culture and then increased rapidly and paralleled the IL-6 release. The addition of recombinant IL-6 during the first days of culture induced a marked proliferation in a dose-dependent manner. PmT-endothelial cells expressed on their surface a high-affinity binding site for IL-6 constituted by both IL-6Ralpha and gp130 transmembrane receptors. The growth-promoting effect of exogenous IL-6 or that released by PmT-endothelial cells was abrogated by mAbs anti-IL-6Ralpha, whereas a mAb recognizing the endothelial cell CD31 molecule was inactive. 15A7 mAb anti-murine IL-6Ralpha was also active in vivo, reducing the number of metastases forming after transplantation of PmT-endothelial cells in DBA/2 mice. 15A7 mAb also increased the survival of mice bearing vascular tumors. We conclude that IL-6 is involved in the progression of vascular tumors induced by PmT, and that the blockage of IL-6-mediated intercellular circuits could be useful in the management of human vascular tumors, including Kaposi's sarcoma.
Giraudo
E
E
Department of Genetics, Biological and Medical Chemistry, University of Torino, Italy.
Arese
M
M
Toniatti
C
C
Strasly
M
M
Primo
L
L
Mantovani
A
A
Ciliberto
G
G
Bussolini
F
F
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000494:pharmacology*; D002461:Cell Line, Transformed; D002472:Cell Transformation, Viral / Q000276:immunology*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000276:immunology* / Q000473:pathology; D005260:Female; D006133:Growth Substances / Q000502:physiology*; D006391:Hemangioma / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D015850:Interleukin-6 / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D011120:Polyomavirus
D000952:Antigens, Polyomavirus Transforming; D006133:Growth Substances; D015850:Interleukin-6