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 induces cytokine secretion, increased cytotoxicity, and proliferation, recent 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 human rNKSF/IL-12 on the formation of colonies by highly enriched hematopoietic 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, erythroid, and myeloid colonies. Therefore, human NKSF/IL-12, like murine NKSF/IL-12, seems to belong to a small group of early acting cytokines, including IL-6, granulocyte-CSF, leukemia-inhibitory factor, and IL-11, which are able to synergize with steel factor and IL-3 to induce proliferation and differentiation of very early hematopoietic progenitor cells. However, in the presence of enriched preparations of NK cells cultured together with the progenitor cells, NKSF/IL-12 inhibits formation of hematopoietic colonies supported by IL-3 and granulocyte-macrophage 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 can be stimulated during bacterial or parasitic infection, it is possible that the direct stimulatory effect of NKSF/IL-12 on hematopoietic progenitor cells and the indirect inhibitory effect mediated by secondary cytokine production by lymphoid cells may play a role in the regulation of physiologic hematopoiesis and in its alterations during infection.
Bellone
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Wistar Institute of Anatomy and Biology, Philadelphia, PA 19104.
Trinchieri
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D015703:Antigens, CD / Q000032:analysis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis; D019002:CD56 Antigen; D016207:Cytokines / Q000378:metabolism; D006410:Hematopoiesis / Q000187:drug effects*; D006801:Humans; D018664:Interleukin-12; D007378:Interleukins / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000502:physiology; D011994:Recombinant Proteins; D013601:T-Lymphocytes / Q000502:physiology
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D019002:CD56 Antigen; D016207:Cytokines; D007378:Interleukins; D011994:Recombinant Proteins; D018664:Interleukin-12