The stimulatory effects of interleukin (IL)-12 on hematopoiesis are antagonized by IL-12-induced interferon gamma in vivo.

Abstract

Interleukin (IL)-12 synergizes with other cytokines to stimulate the proliferation 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 whether 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 microgram/mouse per day) resulted in lower peripheral blood counts and a 2-fold decrease in bone marrow cellularity in wild-type mice, but not in IFN gamma R-/- mice. Bone marrow hematopoietic progenitors were decreased after IL-12 treatment in wild-type mice, but rather increased in IFN gamma R-/- mice. Splenic cellularity was 2.3-fold higher after IL-12 administration in wild-type mice, largely due to natural killer (NK) cell and macrophage infiltration together with some extramedullary hematopoiesis. In IFN gamma R-/- mice, spleen cellularity was less increased, there were fewer infiltrating NK cells, but a strong extramedullary 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 promotes hematopoiesis, consistent with its in vitro activities.

IL-12 Administration Accelerates Autoimmune Diabetes in Both Wild-Type and IFN-γ-Deficient Nonobese Diabetic Mice, Revealing Pathogenic and Protective Effects of IL-12-Induced IFN-γ

“…The decrease of splenic lymphoid cells was accompanied by an elevation of cells expressing high levels of J11d (data not shown), a marker for early hematopoietic cells (32). These progenitors were induced by IL-12 mostly in IFN-␥-sufficient NOD mice (data not shown), in concordance with results obtained in other mouse strains (33,34). Interestingly, the number of CD11c ϩ DCs was increased 2-fold in the spleen of IL-12-treated mice, independently of IFN-␥ (data not shown).…”

Pro-Th1 Cytokines Promote Fas-Dependent Apoptosis of Immature Peripheral Basophils

“…In accordance with this conclusion, medullary cells did not acquire the capacity to kill Fas-transfected targets in response to IL-12 plus IL-18 and produced only minute amounts of IFN-␥ and no detectable TNF-␣ (data not shown). The fact that histamine production is slightly increased when bone marrow cells are treated with IL-12 plus IL-18 is in agreement with the stimulatory effect of IL-12 on hemopoiesis when it is not antagonized by IFN-␥ (29,30).…”

The Toxicology of Interleukin-12: A Review

“…In contrast to wild-type 129/Sv mice, hematopoietic toxicity was not observed in IFN-y R-/-mice (16). Enhanced levels of committed bone marrow hematopoietic progenitor cells were present in IL-12-dosed IFN-~y R-'-mice (16 (25).…”

“…To test the hypothesis that the toxicology of IL-12 is in part due to the synthesis and secretion of high levels of secondary cytokines, IFN-y receptor-deficient (IFN-y R-I-) 129/Sv mice were dosed with 1 pLg/kg/day of rmIL-12 for 4 days (8,16,27). In contrast to wild-type 129/Sv mice, hematopoietic toxicity was not observed in IFN-y R-/-mice (16).…”

“…Preclinical toxicity assessments in mice (8,16,33), guinea pigs (23), squirrel monkeys (45), cynomolgus macaques (23,33), and chimpanzees (T. Anderson, personal communication) have documented adverse IL-12-induced hematopoietic, intestinal, hepatic, and pulmonary effects. The target tissues of IL-12 in various species are summarized in Table I.…”