IL-12 inhibition of endothelial cell functions and angiogenesis depends onlymphocyte-endothelial cell cross-talk

In vivo IL-12-dependent tumor inhibition rests on the ability of IL-12 to a ctivate a CD8-mediated cytotoxicity, inhibit angiogenesis, and cause vascul ar injury. Although in vivo studies have shown that such inhibition stems f rom complex interactions of immune cells and the production of IFN-gamma an d other downstream angiostatic chemokines, the mechanisms involved are stil l poorly defined. Here we show that IL-12 activates an anti-angiogenic prog ram in Con A-activated mouse spleen cells (activated spc) or human PBMC (ac tivated PBMC), The soluble factors they release in its presence arrest the cycle of endothelial cells (EC), inhibit in vitro angiogenesis, negatively modulate the production of matrix metalloproteinase-9, and the ability of E C to adhere to vitronectin and up-regulate ICAM-1 and VCAM-1 expression. Th ese effects do not require direct cell-cell contact, yet result from contin uous interaction between activated lymphoid cells and EC, We used neutraliz ing Abs to show that the IFN-inducible protein-10 and monokine-induced by I FN-gamma chemokines are pivotal in inducing these effects. Experiments with nu/nu mice, nonobese diabetic-SCID mice, or activated spe enriched in spec ific cell subpopulations demonstrated that CD4(+), CD8(+), and NK cells are all needed to mediate the full anti-angiogenetic effect of IL-12.