Interleukin-12 activates NK cells for IFN-gamma -dependent and NKT cells for IFN-gamma -independent antimetastatic activity

Mechanisms involved in the antimetastatic effect of IL-12 were analyzed in a mouse model of experimental metastasis with either syngeneic fibrosarcoma cells colonizing the lungs or syngeneic B cell lymphoma cells colonizing t he liver. IL-12 pretreatment effectively reduced the number of tumor coloni es in both systems. This effect was already manifest 24 hours after tumor c ell injection, indicating a T and B cell-independent mechanism. Therefore, the involvement of NK and alpha beta NKT cells was investigated using mice with defective NK and alpha beta NKT cell functions. Mice with impaired NK functions due to NK cell depletion, were less responsive to the antimetasta tic IL-12 effect. IL-12 treatment failed to inhibit metastasis in beta(2)-m icroglobulin-deficient mice which lack alpha beta NKT cells in addition to having impaired NK cell activity, thus, demonstrating the functional import ance of IL-12-activated NK and alpha beta NKT cells. While the IL-12-induce d antimetastatic effect of NK cells was dependent on IFN-gamma action, IL-1 2 activation of alpha beta NKT cells did not involve IFN-gamma. The neutral ization of IFN-gamma or the use of IFN-gamma receptor-deficient mice did no t alter the IL-12-induced effect in the absence of NK cells. Activation of effector cells of the innate immune system, such as NK and alpha beta NKT c ells, seems to be the main mechanism for the antimetastatic effect of IL-12 .