THE BIOLOGICAL CONSEQUENCES OF EXCESS GM-CSF LEVELS IN TRANSGENIC MICE ALSO LACKING HIGH-AFFINITY RECEPTORS FOR GM-CSF

Citation
D. Metcalf et al., THE BIOLOGICAL CONSEQUENCES OF EXCESS GM-CSF LEVELS IN TRANSGENIC MICE ALSO LACKING HIGH-AFFINITY RECEPTORS FOR GM-CSF, Leukemia, 12(3), 1998, pp. 353-362
Citations number
26
Categorie Soggetti
Hematology,Oncology
Journal title
ISSN journal
08876924
Volume
12
Issue
3
Year of publication
1998
Pages
353 - 362
Database
ISI
SICI code
0887-6924(1998)12:3<353:TBCOEG>2.0.ZU;2-A
Abstract
GM-CSF transgenic mice were crossed with mice with homozygous inactiva tion of the gene encoding the common beta chain (beta c) of the CM-CSF receptor to produce mice with constitutively elevated GM-CSF levels b ut no high-affinity GM-CSF receptors. GM-CSF transgenic beta -/- mice had exceptionally elevated serum GM-CSF levels but failed to develop t he abnormal peritoneal cell population, eye destruction or tissue lesi ons characteristic of GM-CSF transgenic beta c +/+ mice. The alveolar proteinosis of beta c -/- mice was not altered in GM-CSF transgenic be ta c -/- mice. Levels of GM-CSF mRNA in transgenic GMCSF beta c -/- we re elevated but lower than in transgenic beta +/+ mice and the higher serum GM-CSF levels were traced in part to the longer serum half-life of GM-CSF in beta c -/- than in beta c +/+ mice although urinary loss of GM-CSF was higher in beta c -/- than in +/+ mice. The data indicate that the transgenic phenotype was due to stimulation by GM-CSF and no t an insertional effect, that low-affinity receptors are not capable o f initiating tissue pathology even in the presence of excess GM-CSF le vels and that autocrine production of GM-CSF by GM-CSF-responsive cell s also fails to induce changes in these cells. The results support cur rent dogma that the action of polypeptide regulators is mediated exclu sively by activation of high-affinity membrane receptors.