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The biological consequences of excess GM-CSF levels in transgenic mice also lacking high-affinity receptors for
D Metcalf1, S Mifsud, L Di Rago
1The Walter and Eliza Hall Institute of Medical Research, PO Royal Melbourne Hospital, Victoria, Australia.
Abstract:
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.
Insights
Granulocyte-macrophage colony-stimulating factor (GM-CSF) requires high-affinity receptors to trigger its pathological effects. Even with elevated GM-CSF levels, low-affinity receptors do not cause tissue damage.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a cytokine crucial for immune cell development and function.
- Dysregulation of GM-CSF signaling is implicated in various inflammatory and autoimmune diseases.
- Understanding the specific receptor interactions mediating GM-CSF's effects is vital for therapeutic development.
Purpose of the Study:
- To investigate the role of high-affinity GM-CSF receptors in mediating the pathological effects of elevated GM-CSF levels.
- To determine if low-affinity GM-CSF receptors can initiate tissue pathology.
- To elucidate the necessity of specific receptor engagement for GM-CSF-induced cellular changes.
Main Methods:
- Generation of GM-CSF transgenic mice crossed with mice lacking the common beta chain (beta c) of the GM-CSF receptor (GM-CSF transgenic beta c -/- mice).
- Analysis of serum GM-CSF levels, mRNA expression, and pharmacokinetic properties (serum half-life, urinary loss).
- Phenotypic characterization of GM-CSF transgenic beta c -/- mice, including peritoneal cell populations, ocular tissues, and lung pathology, compared to control GM-CSF transgenic mice (beta c +/+).
Main Results:
- GM-CSF transgenic beta c -/- mice exhibited significantly elevated serum GM-CSF but lacked the characteristic pathology (abnormal peritoneal cells, eye destruction, tissue lesions) seen in GM-CSF transgenic beta c +/+ mice.
- Alveolar proteinosis observed in beta c -/- mice was not altered by GM-CSF transgenesis.
- Elevated GM-CSF mRNA levels in GM-CSF transgenic beta c -/- mice were lower than in beta c +/+ mice, with increased serum half-life and urinary loss contributing to higher serum GM-CSF.
- Low-affinity receptor signaling, even with excess GM-CSF, did not induce tissue pathology or cellular changes.
Conclusions:
- The pathological phenotype observed in GM-CSF transgenic mice is directly mediated by GM-CSF acting through high-affinity receptors.
- Low-affinity GM-CSF receptors are insufficient to initiate tissue pathology, irrespective of GM-CSF concentration.
- Autocrine GM-CSF production by GM-CSF-responsive cells also fails to induce cellular changes without high-affinity receptor activation.
- These findings strongly support the model that polypeptide regulator actions are exclusively mediated by high-affinity membrane receptors.