Abstract
GM-CSF transgenic mice were crossed with mice with homozygous inactivation of the gene encoding the common β chain (βc) of the GM-CSF receptor to produce mice with constitutively elevated GM-CSF levels but no high-affinity GM-CSF receptors. GM-CSF transgenic βc −/− 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 βc +/+ mice. The alveolar proteinosis of βc −/− mice was not altered in GM-CSF transgenic βc −/− mice. Levels of GM-CSF mRNA in transgenic GM-CSF βc −/− were elevated but lower than in transgenic β +/+ mice and the higher serum GM-CSF levels were traced in part to the longer serum half-life of GM-CSF in βc −/− than in βc +/+ mice although urinary loss of GM-CSF was higher in βc −/− 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-CSF-responsive 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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Metcalf, D., Mifsud, S., Rago, L. et al. The biological consequences of excess GM-CSF levels in transgenic mice also lacking high-affinity receptors for GM-CSF. Leukemia 12, 353–362 (1998). https://doi.org/10.1038/sj.leu.2400926
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DOI: https://doi.org/10.1038/sj.leu.2400926
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