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 the liver. IL-12 pretreatment effectively reduced the number of tumor colonies in both systems. This effect was already manifest 24 hours after tumor cell injection, indicating a T and B cell-independent mechanism. Therefore, the involvement of NK and alphabetaNKT cells was investigated using mice with defective NK and alphabetaNKT cell functions. Mice with impaired NK functions due to NK cell depletion, were less responsive to the antimetastatic IL-12 effect. IL-12 treatment failed to inhibit metastasis in beta2-microglobulin-deficient mice which lack alphabetaNKT cells in addition to having impaired NK cell activity, thus, demonstrating the functional importance of IL-12-activated NK and alphabetaNKT cells. While the IL-12-induced antimetastatic effect of NK cells was dependent on IFN-gamma action, IL-12 activation of alphabetaNKT cells did not involve IFN-gamma. The neutralization of IFN-gamma or the use of IFN-gamma receptor-deficient mice did not 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 alphabetaNKT cells, seems to be the main mechanism for the antimetastatic effect of IL-12.
Hafner
M
M
Tumorimmunology, Institute of Pathology, University of Regensburg, F. J.-Strauss Allee 11, D- 93042 Regensburg, Germany.
Falk
W
W
Echtenacher
B
B
Männel
D N
DN
D000818:Animals; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D005260:Female; D005354:Fibrosarcoma / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D017353:Gene Deletion; D007371:Interferon-gamma / Q000276:immunology* / Q000502:physiology; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D008113:Liver Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000473:pathology / Q000556:secondary; D008175:Lung Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000473:pathology / Q000556:secondary; D008223:Lymphoma / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D009362:Neoplasm Metastasis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D009368:Neoplasm Transplantation; D017471:Receptors, Interferon / Q000235:genetics / Q000502:physiology; D015375:Receptors, Interleukin-2 / Q000737:chemistry / Q000276:immunology / Q000502:physiology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay; D001613:beta 2-Microglobulin / Q000235:genetics / Q000502:physiology; D000096743:Interferon gamma Receptor
D007371:Interferon-gamma; D018664:Interleukin-12; D017471:Receptors, Interferon; D015375:Receptors, Interleukin-2; D011994:Recombinant Proteins; D001613:beta 2-Microglobulin; D000096743:Interferon gamma Receptor