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 polyo mavirus (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 mesen chymal cells, In murine endothelial cells, PmT induces modification of the expression of genes, including; that of IL-6. Since IL-6 is a ple iotrophic cytokine that also regulates endothelial cell functions rela ted to angiogenesis, we studied the relevance of IL-6 in the tumorigen icity of PmT-endothelial cells. In vitro studies demonstrated that the spontaneous PmT-endothelial cell proliferation rate was slow during t he first 6 days of culture and then increased rapidly and paralleled t he IL-6 release. The addition of recombinant IL-6 during the first day s of culture induced a marked proliferation in a dose-dependent manner . PmT-endothelial cells expressed on their surface a high-affinity bin ding site for IL-6 constituted by both IL-6R alpha and gp130 transmemb rane receptors. The growth-promoting effect of exogenous IL-6 or that released by PmT-endothelial cells was abrogated by mAbs anti-IL-6R alp ha, whereas a mAb recognizing the endothelial cell CD31 molecule was i nactive, 15A7 mAb anti-murine IL-6R alpha was also active in vivo, red ucing the number of metastases forming after transplantation of PmT-en dothelial cells in DBA/2 mice. 15A7 mAb also increased the survival of mice bearing vascular tumors, We conclude that IL-6 is involved in th e progression of vascular tumors induced by PmT, and that the blockage of IL-6-mediated intercellular circuits could be useful in the manage ment of human vascular tumors, including Kaposi's sarcoma.