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Published online before print July 25, 2007

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(Journal of Leukocyte Biology. 2007;82:915-925.)
© 2007 by Society for Leukocyte Biology

Macrophage-colony stimulating factor is required for the production of neutrophil-promoting activity by mouse embryo fibroblasts deficient in G-CSF and GM-CSF

Hui Hua Zhang^*, Sunanda Basu^*,, Fenqiang Wu^*,, C. Glenn Begley, Christiaan J. M. Saris, Ashley R. Dunn^*, Antony W. Burgess^* and Francesca Walker^*,1

^* Ludwig Institute for Cancer Research, Melbourne Tumor Biology Branch, Melbourne, Victoria, Australia;
Walther Oncology Center, Indiana University School of Medicine, Research Institute No. 2, Indianapolis, Indiana, USA;
Commonwealth Serum Laboratories, Parkville, Victoria, Australia; and
Amgen Inc., Thousand Oaks, California, USA

¹ Correspondence: Ludwig Institute for Cancer Research, P.O. Box 2008 RMH, Melbourne, Victoria 3050, Australia. E-mail: francesca.walker{at}ludwig.edu.au

G-CSF and GM-CSF play important roles in regulating neutrophil production, survival, differentiation, and function. However, we have shown previously that G-CSF/GM-CSF double-deficient [knockout (KO)] mice still develop a profound neutrophilia in bone marrow and blood after infection with Candida albicans. This finding suggests the existence of other systems, which can regulate emergency neutrophil production. We have now developed an "in vitro" technique to detect and characterize a neutrophil-promoting activity (NPA) in the media conditioned by mouse embryonic fibroblasts (MEFs) derived from G-CSF^–/–/GM-CSF^–/– mice. NPA is produced in vitro by the MEFs after stimulation with LPS or heat-inactivated C. albicans. Although M-CSF added directly to bone marrow cultures does not sustain granulocyte production, our studies indicate that production of NPA requires activation of the M-CSF receptor (c-fms). First, G-CSF^–/–/GM-CSF^–/– MEFs produce high levels of NPA after stimulation with LPS or C. albicans, and G-CSF/GM-CSF/M-CSF triple-KO MEFs do not. Second, the production of NPA by the G-CSF^–/–/GM-CSF^–/– MEFs is reduced significantly upon incubation with neutralizing antibodies to M-CSF or c-fms. Third, NPA production by G-CSF^–/–/GM-CSF^–/–/M-CSF^–/– fibroblasts is enhanced by supplementing culture medium with M-CSF. Thus, stimulation of c-fms by M-CSF is a prerequisite for the production of NPA.

Key Words: cytokines • granulopoiesis • knockout mice

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