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 acti vated T cells and exhibit similar biologic activities by signaling thr ough a common receptor subunit (beta c), Mice lacking beta c show a pu lmonary alveolar proteinosis-like disease and reduced numbers of perip heral 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 subun it 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 b y functional redundancy between IL-3 and GM-CSF. To clarify the role o f the entire lL-3/GM-CSF/IL-5 system in hematopoiesis in vivo, we cros sed the beta c mutant mice with mice deficient for IL-3 ligand to gene rate mice lacking the entire IL-3/GM-CSF/IL-5 functions. The double-mu tant mice were apparently normal and fertile. The severity of the lung pathology in the beta c/IL-3 double-mutant mice was the same as that of the beta c mutant mice, The double-mutant mice showed normal hemody namic parameters except for reduced numbers of eosinophils and the lac k 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 m ice to Listeria monocytogenes was normal, as was hematopoietic recover y after administration of the cytotoxic drug, 5-fluorouracil, Although it has been believed that IL-3/GM-CSF/IL-5 produced by activated T ce lls 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 s tate, Thus, there must be an alternative mechanism to produce blood ce lls in both situations. (C) 1996 by The American Society of Hematology .