THE STIMULATORY EFFECTS OF INTERLEUKIN (IL)-12 ON HEMATOPOIESIS ARE ANTAGONIZED BY IL-12-INDUCED INTERFERON-GAMMA IN-VIVO

Interleukin (IL)-12 synergizes with other cytokines to stimulate the p roliferation and differentiation of early hematopoietic progenitors in vitro. However, in vivo administration of IL-12 decreases peripheral blood counts and bone marrow hematopoiesis. Here, we used interferon ( IFN) gamma receptor-deficient (IFN gamma R(-/-)) mice to investigate w hether the in vivo inhibition of hematopoiesis by IL-12 is indirectly mediated by IL-12-induced IFN-gamma. IL-12 administered for 4 d (1 mu g/mouse per day) resulted in lower peripheral blood counts and a 2-fol d decrease in bone marrow cellularity in wild-type mice, but not in IF N gamma R(-/-) mice. Bone marrow hematopoietic progenitors were decrea sed after IL-12 treatment in wild-type mice, but rather increased in I FN gamma R(-/-) mice. Splenic cellularity was 2.3-fold higher after IL -12 administration in wild-type mice, largely due to natural killer (N K) cell and macrophage infiltration together with some extramedullary hematopoiesis. In IFN gamma R(-/-) mice, spleen cellularity was less i ncreased, there were fewer infiltrating NK cells, but a strong extrame dullary hematopoiesis. Thus, alterations mediated by IL-12-induced IFN -gamma include reduction in bone marrow cellularity and hematopoietic progenitors, as well as pronounced splenomegaly, largely caused by NK cell infiltration. In the absence of IFN-gamma signaling, IL-12 promot es hematopoiesis, consistent with its in vitro activities.