DUAL STIMULATORY AND INHIBITORY EFFECT OF NK CELL STIMULATORY FACTOR IL-12 ON HUMAN HEMATOPOIESIS

NK cell stimulatory factor, or IL-12 (NKSF/IL-12), is a heterodimeric cytokine produced by monocyte-macrophages, B cells, and possibly other accessory cell types. Although the major biologic effects of NKSF/IL- 12 have been demonstrated on mature T and NK cells, in which it induce s cytokine secretion, increased cytotoxicity, and proliferation, recen t evidence in the murine system has suggested that NKSF/IL-12 may play a role in the differentiation of early lymphohematopoietic progenitor cells and thymocytes. In this paper, we have analyzed the effect of h uman rNKSF/IL-12 on the formation of colonies by highly enriched hemat opoietic progenitor cells from human peripheral blood and bone marrow. At concentrations between 1 and 10 ng/ml, NKSF/IL-12 synergizes with a combination of steel factor and IL-3 to induce formation of mixed, e rythroid, and myeloid colonies. Therefore, human NKSF/IL-12, like muri ne NKSF/IL-12, seems to belong to a small group of early acting cytoki nes, including IL-6, granulocyte-CSF, leukemia-inhibitory factor, and IL-11, which are able to synergize with steel factor and IL-3 to induc e proliferation and differentiation of very early hematopoietic progen itor cells. However, in the presence of enriched preparations of NK ce lls cultured together with the progenitor cells, NKSF/IL-12 inhibits f ormation of hematopoietic colonies supported by IL-3 and granulocyte-m acrophage CSF, by inducing production of IFN-gamma and TNF-alpha, two cytokines with synergistic inhibitory effects on hematopoietic colony formation. Because cell types that are able to produce NKSF/IL-12 are present in normal bone marrow and NKSF/IL-12 production in vivo and ca n be stimulated during bacterial or parasitic infection, it is possibl e that the direct stimulatory effect of NKSF/IL-12 on hematopoietic pr ogenitor cells and the indirect inhibitory effect mediated by secondar y cytokine production by lymphoid cells may play a role in the regulat ion of physiologic hematopoiesis and in its alterations during infecti on.