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Updated: Jul 8, 2026
Proliferation and Differentiation of Murine Myeloid Precursor 32D/G-CSF-R Cells
Published on: February 21, 2018
IL6/sIL6R complex contributes to emergency granulopoietic responses in G-CSF- and GM-CSF-deficient mice
Francesca Walker1, Hui-Hua Zhang, Vance Matthews
1Ludwig Institute for Cancer Research, Melbourne Tumor Biology Branch, Melbourne, Victoria, Australia. francesca.walker@ludwig.edu.au
Insights
Mice lacking G-CSF and GM-CSF still produce neutrophils when infected. This response is driven by an alternative pathway involving interleukin-6 (IL6) and its soluble receptor, revealing a new mechanism for granulocyte production.
Area of Science:
- Immunology
- Hematology
- Cell Biology
Background:
- Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) are critical for neutrophil production.
- Mice lacking both G-CSF and GM-CSF exhibit impaired neutrophil development but still mount a response to pathogens.
Purpose of the Study:
- To investigate the mechanism behind neutrophil production in G-CSF and GM-CSF double knockout mice.
- To identify the specific factors responsible for neutrophil promoting activity (NPA) in these mice.
Main Methods:
- Utilized an in vitro system with conditioned media from stimulated G-CSF(-/-)/GM-CSF(-/-) cells.
- Assessed the role of interleukin-6 (IL6) and its receptor (IL6R) using antibodies and soluble gp130.
- Investigated the effects of Hyper-IL6 and soluble IL6R on bone marrow cells.
Main Results:
- Neutrophil promoting activity (NPA) in the conditioned media was dependent on IL6.
- NPA was abolished by soluble gp130 and could be depleted by an anti-IL6R antibody.
- The IL6/soluble IL6 receptor (sIL6R) complex was identified as the primary mediator of NPA.
Conclusions:
- An alternative pathway for granulocyte production exists, independent of G-CSF and GM-CSF.
- The IL6/sIL6R complex is the major driver of this alternative pathway.
- This pathway is activated upon pathogen exposure, highlighting its role in innate immunity.
Abstract:
Mice defective in both granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) have severely impaired neutrophil production and function, yet these mice respond to acute pathogen challenge with a significant neutrophil response. We have recently reported the development of an in vitro system to detect granulopoietic cytokines secreted from cells isolated from G-CSF, GM-CSF double knockout mice. The conditioned media produced by these cells after stimulation with lipopolysaccharide or Candida albicans supports the production and differentiation of granulocytes (ie, the conditioned media contains neutrophil promoting activity [NPA]). We now show that the NPA in the G-CSF(-/-)/GM-CSF(-/-) conditioned media requires interleukin-6 (IL6), is abolished by soluble gp130, and can be specifically immunodepleted by an anti-IL6R antibody. NPA effects on bone marrow cells are also mimicked by Hyper-IL6, and the soluble IL6R is present in NPA. These results show that the IL6/sIL6R complex is the major effector of NPA. NPA production by mice defective for both G-CSF and GM-CSF uncovers an alternative pathway to granulocyte production, which is activated after exposure to pathogens.
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