A purified recombinant human granulocyte-macrophage colony stimulating factor (rH GM-CSF) was a powerful stimulator of mature human eosinophils and neutrophils. The purified rH GM-CSF enhanced the cytotoxic activity of neutrophils and eosinophils against antibody-coated targets, stimulated phagocytosis of serum-opsonized yeast by both cell types in a dose-dependent manner, and stimulated neutrophil-mediated iodination in the presence of zymosan. In addition, rH GM-CSF enhanced Nformylmethionylleucylphenylalanine(FMLP)-stimulated degranulation ofCytochalasin B pretreated neutrophils and FMLPstimulated superoxide production. In contrast, rH GM-CSF did not promote adherence of granulocytes to endothelial cells or plastic surfaces. rH GM-CSF selectively enhanced the surface expression of granulocyte functional antigens 1 and 2, and the Mol antigen. rH GM-CSF induced morphological changes and enhanced the survival of both neutrophils and eosinophils by 6 and 9 h, respectively. These experiments show that granulocytemacrophage colony stimulating factor can selectively stimulate mature granulocyte function.
Recombinant human granulocyte-macrophage colony-stimulating factor (rH GM-CSF) was purified to homogeneity from medium conditioned by COS cells transfected with a cloned human GM-CSF cDNA and shown to be an effective proliferative stimulus in human marrow cultures for GM and eosinophil colony formation. The specific activity of purified rH GM- CSF in human marrow cultures was calculated to be at least 4 X 10(7) U/mg protein. Clone transfer experiments showed that this proliferation was due to direct stimulation of responding clonogenic cells. Acting alone, rH GM-CSF did not stimulate erythroid colony formation, but in combination with erythropoietin, increased erythroid and multipotential colony formation in cultures of peripheral blood cells. rH GM-CSF had no proliferative effects on adult or fetal murine hematopoietic cells, did not induce differentiation in murine myelomonocytic WEHI-3B cells, and was unable to stimulate the survival or proliferation of murine hematopoietic cell lines dependent on murine multi-CSF (IL 3). rH GM- CSF stimulated antibody-dependent cytolysis of tumor cells by both mature human neutrophils and eosinophils and increased eosinophil autofluorescence and phagocytosis by neutrophils. From a comparison of these effects with those of semipurified preparations of human CSF alpha and -beta, it was concluded that rH GM-CSF exhibited all the biologic activities previously noted for CSF alpha.
IL-1 is released by activated monocytes and is thought to be a key mediator of the host immune response. The availability of the purified and, more recently, recombinant IL-1 has allowed the characterization of other biological properties of this molecule. Thus, IL-1 is thought to have the same properties as hemopoietic 1, a growth factor that has been shown to act on primitive murine hemopoietic cells. Here we report that rIL-1 acts synergistically with granulocyte/macrophage CSF (GM-CSF) or granulocyte CSF in the stimulation of clonogenic cells from many patients with acute myeloblastic leukemia (AML). Although IL-1 by itself has no effect on AML blasts, it can support colony formation under conditions where there is detectable production of endogenous GM-CSF. IL-1 also promotes the growth of multipotential progenitors from normal human bone marrow cells in the presence of GM-CSF. These observations support the hypothesis that in the hemopoietic system, IL-1 has a selective effect on primitive precursors.
The proteins encoded by the ras oncogene are thought to trigger expression of the transformed phenotype in some types of cancer cells. In human cells, the ras protein family consists of several members including normal (proto-oncogene) and mutant (oncogene) forms. In general, the proto-oncogene forms are thought to be involved in the normal growth control of cells, while the mutant forms (which apparently result from somatic mutation of the normal ras genes) appear to be responsible, in part, for the loss of normal growth control. On microinjection into living normal cells, the purified ras oncogene protein (p21) induces a characteristic loss of growth control in cells within several hours. The mutant forms of the different ras proteins typically contain a single amino-acid change, usually at position 12 or less frequently at position 61. Here we report that microinjection of antibodies specific for amino acid 12 of the oncogenic v-Ki-ras protein into cells transformed by this protein causes a transient reversion of the cells to a normal phenotype. The fact that this antibody inhibits binding of GTP to the v-Ki-ras protein supports the notion that GTP binding is essential to the transforming function of this oncogene product.
The blast stem cells of acute myeloblastic leukemia (AML) respond in cell culture to growth factors by both self-renewal and terminal divisions. Both of these functions have been shown to be stimulated by the recombinant growth factors granulocyte-macrophage colony- stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF). In this paper, recombinant gibbon interleukin-3 (IL-3), homologous to human IL-3, was tested on blast cells and compared with the effects of GM-CSF, G-CSF, and medium conditioned by the bladder cell line 5637 (5637-CM). We found that IL-3 was an effective stimulator of blast renewal and terminal divisions. However, great patient-to-patient variation was found. A graphic method of presenting complex comparisons between growth factors is also included.
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