Administration of recombinant interleukin-12 to mice suppresses hematopoiesis in the bone marrow but enhances hematopoiesis in the spleen.
Although IL-12 has been reported to synergize with c-kit ligand (KL) in promoting hematopoietic stem cell proliferation in vitro, administration of recombinant mouse IL-12 (rIL-12) to normal mice caused a dose- and time-dependent anemia, leukopenia, and thrombocytopenia in vivo. Decreased numbers of bone marrow cells were recovered from the tibiae of IL-12-treated mice, and histologic examination of the marrow revealed a loss of mature neutrophils and red blood cell precursors. However, simultaneously with the suppression of hematopoiesis in the bone marrow, the IL-12-treated mice developed splenomegaly, which was largely caused by a marked enhancement of splenic extramedullary hematopoiesis of the erythroid, myeloid, and megakaryocytic lineages. These histologic observations were confirmed by colony-forming cell assays in which administration of IL-12 was shown to cause a time-dependent decrease in bone marrow CFU-GM, CFU-E, and BFU-E hematopoietic colony-forming cells while causing an increase in splenic CFU-GM and BFU-E colony-forming cells. All these effects were reversible upon cessation of IL-12 treatment. The observation that in IL-12-treated mice hematopoiesis was suppressed in the marrow but enhanced in the spleen suggests that myelosuppression was not caused by a direct effect of IL-12 on hematopoietic progenitors. It seems likely that myelosuppression was caused instead by an IL-12-induced alteration in the local environment of the marrow.
Tare
N S
NS
Department of Inflammation/Autoimmune Diseases, Hoffmann-La Roche, Inc., Nutley, New Jersey 07110, USA.
Bowen
S
S
Warrier
R R
RR
Carvajal
D M
DM
Benjamin
W R
WR
Riley
J H
JH
Anderson
T D
TD
Gately
M K
MK
D000740:Anemia / Q000139:chemically induced; D000818:Animals; D001853:Bone Marrow / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006410:Hematopoiesis / Q000187:drug effects*; D006411:Hematopoiesis, Extramedullary / Q000187:drug effects*; D018664:Interleukin-12 / Q000494:pharmacology*; D007970:Leukopenia / Q000139:chemically induced; D051379:Mice; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins / Q000494:pharmacology; D012016:Reference Values; D013154:Spleen / Q000187:drug effects*; D013921:Thrombocytopenia / Q000139:chemically induced
D011994:Recombinant Proteins; D018664:Interleukin-12