Interleukin-12-induced interferon-gamma inhibits hematopoiesis in vivo in mice.
In vivo administration of interleukin-12 decreases peripheral blood counts and bone marrow hematopoiesis, although in vitro IL-12 was shown to synergize with other cytokines to stimulate the proliferation and differentiation of early hematopoietic progenitors. We investigated whether the in vivo inhibition of hematopoiesis by IL-12 is indirectly mediated by IL-12-induced IFN-gamma. IL-12 was administered to wild-type or IFN-gamma receptor deficient (IFN gamma R-/-) mice. IL-12 treatment resulted in lower peripheral blood counts and a twofold decrease in bone marrow cellularity and hematopoietic progenitors in wild-type mice, but not in IFN gamma R-/- mice. Splenic weight and cellularity were dramatically increased after IL-12 administration in wild-type mice and somewhat less in IFN gamma R-/- mice. The increase was predominantly due to NK cell and macrophage infiltration in wild-type mice, and strong extramedullary hematopoiesis in IFN gamma R-/- mice. Thus, the reduction in total bone marrow cells and hematopoietic progenitor numbers following IL-12 treatment are largely indirect, mediated by IL-12-induced IFN gamma. In the absence of IFN-gamma signaling, IL-12 promotes both bone marrow and splenic hematopoiesis, consistent with its in vitro activities.
Quesniaux
V F
VF
Sandoz Pharma Ltd., Basel, Switzerland.
Ryffel
B
B
D000818:Animals; D015703:Antigens, CD / Q000502:physiology; D001854:Bone Marrow Cells; D006410:Hematopoiesis; D006801:Humans; D007371:Interferon-gamma / Q000502:physiology*; D018664:Interleukin-12 / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D017471:Receptors, Interferon / Q000502:physiology; D013154:Spleen / Q000166:cytology; D000096743:Interferon gamma Receptor
D015703:Antigens, CD; D007371:Interferon-gamma; D018664:Interleukin-12; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor