The biological consequences of excess GM-CSF levels in transgenic mice also lacking high-affinity receptors for GM-CSF.
GM-CSF transgenic mice were crossed with mice with homozygous inactivation of the gene encoding the common beta chain (beta 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 beta 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 beta c +/+ mice. The alveolar proteinosis of beta c -/- mice was not altered in GM-CSF transgenic beta c -/- mice. Levels of GM-CSF mRNA in transgenic GM-CSF beta c -/- were 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 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.
Metcalf
D
D
The Walter and Eliza Hall Institute of Medical Research, PO Royal Melbourne Hospital, Victoria, Australia.
Mifsud
S
S
Di Rago
L
L
Robb
L
L
Nicola
N A
NA
Alexander
W
W
D000818:Animals; D003433:Crosses, Genetic; D005123:Eye / Q000473:pathology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D006720:Homozygote; D007958:Leukocyte Count; D017737:Macrophages, Peritoneal / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009928:Organ Specificity; D016133:Polymerase Chain Reaction; D011649:Pulmonary Alveolar Proteinosis / Q000235:genetics / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000172:deficiency*; D014158:Transcription, Genetic
D012333:RNA, Messenger; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor