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
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.