The intraperitoneal injection into mice of casein preparations containing bacteria induced a rapid accumulation of neutrophils within 3 hours due to selective release of mature cells from the bone marrow. Significant increases in the concentrations of granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) occurred in the peritoneal cavity during the process, but the intraperitoneal injection of neither CSF induced a significant accumulation of neutrophils and the coinjection of G-CSF and casein failed to enhance the neutrophil response. The lack of involvement of either CSF in the neutrophil migration was confirmed by the development of typical neutrophil exudates when casein was injected into mice with inactivation of the genes encoding GM-CSF, G-CSF, or the beta-common chain of the GM-CSF receptor. However, preinjection of G-CSF increased the number of marrow neutrophils available for migration and did result in increased numbers of neutrophils in the peritoneal cavity after casein injection. Typical eosinophil inflammatory responses to the injection of casein or thioglycollate occurred in GM-CSF -/-mice but not in beta c -/-mice, suggesting that interleukin-5 was necessary for this response.
The cloned pro-B-lymphocyte murine leukemic cell line GB2, was established from a leukemic Max41 x E -myc double transgenic mouse. Its Igh alleles are rearranged and its surface markers are primarily B-lymphoid, but a small proportion of the cells also express surface Gr-1 and some cells develop the morphology of maturing granulocytes. The cell line grows continuously in suspension culture without the addition of growth factors, but expresses mRNA for M-CSF, TPO and Flt-3-ligand. When stimulated in agar cultures by GM-CSF, G-CSF, M-CSF, IL-3, SCF, IL-6, leukemia inhibitory factor (LIF), IL-5 or IFN␥, GB2 cells generated blast colonies or colonies of maturing granulocytes and macrophages. There was a striking similarity in colony types, relative colony numbers and maturation of colony cells to those formed by normal bone marrow cells in response to the same stimuli. GB2 blast colony-forming cells exhibited self-renewal as well as an ability to form granulocytemacrophage colony-forming progeny, with evidence that a hierarchical sequence of clonogenic cells is generated in the cell line even after subcloning. Factor-specific maturation was clearly initiated by the action of the added growth factors. In contrast, FACS-sorting experiments showed that commitment to various types of colony-forming cell occurs in maintenance suspension cultures in the apparent absence of potentially relevant growth factors. Leukemia (2000) 14, 1785-1795.
GM-CSF transgenic mice were crossed with mice with homozygous inactivation of the gene encoding the common  chain (c) of the GM-CSF receptor to produce mice with constitutively elevated GM-CSF levels but no high-affinity GM-CSF receptors. GM-CSF transgenic c ؊/؊ mice had exceptionally elevated serum GM-CSF levels but failed to develop the abnormal peritoneal cell population, eye destruction or tissue lesions characteristic of GM-CSF transgenic c ؉/؉ mice. The alveolar proteinosis of c ؊/؊ mice was not altered in GM-CSF transgenic c ؊/؊ mice. Levels of GM-CSF mRNA in transgenic GM-CSF c ؊/؊ were elevated but lower than in transgenic  ؉/؉ mice and the higher serum GM-CSF levels were traced in part to the longer serum half-life of GM-CSF in c ؊/؊ than in c ؉/؉ mice although urinary loss of GM-CSF was higher in c ؊/؊ than in ؉/؉ mice. The data indicate that the transgenic phenotype was due to stimulation by GM-CSF and not an insertional effect, that low-affinity receptors are not capable of initiating tissue pathology even in the presence of excess GM-CSF levels and that autocrine production of GM-CSF by GM-CSFresponsive cells also fails to induce changes in these cells. The results support current dogma that the action of polypeptide regulators is mediated exclusively by activation of high-affinity membrane receptors.
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