Hematopoiesis in mice lacking the entire granulocyte-macrophage colony-stimulating factor/interleukin-3/interleukin-5 functions.
Interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-5 are major hematopoietic cytokines produced by activated T cells and exhibit similar biologic activities by signaling through a common receptor subunit (beta c). Mice lacking beta c show a pulmonary alveolar proteinosis-like disease and reduced numbers of peripheral eosinophils, which are explained by the lack of GM-CSF and IL-5 function, respectively. However, beta c-deficient hematopoietic cells do respond to IL-3 normally, probably through an additional beta subunit of the IL-3 receptor (beta IL3) that is present in the mouse. Thus, almost normal hematopoiesis in beta c-deficient mice may be caused by functional redundancy between IL-3 and GM-CSF. To clarify the role of the entire IL-3/GM-CSF/IL-5 system in hematopoiesis in vivo, we crossed the beta c mutant mice with mice deficient for IL-3 ligand to generate mice lacking the entire IL-3/GM-CSF/IL-5 functions. The double-mutant mice were apparently normal and fertile. The severity of the lung pathology in the beta c/IL-3 double-mutant mice showed normal hemodynamic parameters except for reduced numbers of eosinophils and the lack of eosinophilic response to parasites, which were also found in beta c mutant mice. The immune response of the beta c/IL-3 double-mutant mice to Listeria mono-cytogenes was normal, as was hematopoietic recovery after administration of the cytotoxic drug, 5-fluorouracil. Although it has been believed that IL-3/GM-CSF/IL-5 produced by activated T cells play a major role in expansion of hematopoietic cells in emergency, our results indicate that the entire function of IL-3/GM-CSF/IL-5 is dispensable for hematopoiesis in emergency as well as in the steady state. Thus, there must be an alternative mechanism to produce blood cells in both situations.
Nishinakamura
R
R
DNAX Research Institute, Palo Alto, CA 94304-1104, USA.
Miyajima
A
A
Mee
P J
PJ
Tybulewicz
V L
VL
Murray
R
R
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D003433:Crosses, Genetic; D004804:Eosinophils / Q000473:pathology; D005472:Fluorouracil / Q000633:toxicity; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000502:physiology*; D006410:Hematopoiesis; D007121:Immunocompetence; D007377:Interleukin-3 / Q000502:physiology*; D015848:Interleukin-5 / Q000502:physiology*; D007970:Leukopenia / Q000235:genetics / Q000473:pathology; D008088:Listeriosis / Q000276:immunology; D008171:Lung Diseases / Q000235:genetics* / Q000473:pathology; D016676:Macrophages, Alveolar / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009559:Nippostrongylus; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics; D018123:Receptors, Interleukin / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics; D016185:Receptors, Interleukin-3 / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics; D053649:Receptors, Interleukin-5; D017206:Strongylida Infections / Q000276:immunology
D007377:Interleukin-3; D015848:Interleukin-5; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D018123:Receptors, Interleukin; D016185:Receptors, Interleukin-3; D053649:Receptors, Interleukin-5; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D005472:Fluorouracil