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IL-34 and M-CSF share the receptor Fms but are not identical in biological activity and signal activation
1Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, Kumamoto, Japan.
Abstract:
Macrophage colony-stimulating factor (M-CSF) regulates the production, survival and function of macrophages through Fms, the receptor tyrosine kinase. Recently, interleukin-34 (IL-34), which shares no sequence homology with M-CSF, was identified as an alternative Fms ligand. Here, we provide the first evidence that these ligands indeed resemble but are not necessarily identical in biological activity and signal activation. In culture systems tested, IL-34 and M-CSF showed an equivalent ability to support cell growth or survival. However, they were different in the ability to induce the production of chemokines such as MCP-1 and eotaxin-2 in primary macrophages, the morphological change in TF-1-fms cells and the migration of J774A.1 cells. Importantly, IL-34 induced a stronger but transient tyrosine phosphorylation of Fms and downstream molecules, and rapidly downregulated Fms. Even in the comparison of active domains, these ligands showed no sequence homology including the position of cysteines. Interestingly, an anti-Fms monoclonal antibody (Mab) blocked both IL-34-Fms and M-CSF-Fms binding, but another MAb blocked only M-CSF-Fms binding. These results suggested that IL-34 and M-CSF differed in their structure and Fms domains that they bound, which caused different bioactivities and signal activation kinetics/strength. Our findings indicate that macrophage phenotype and function are differentially regulated even at the level of the single receptor, Fms.
Insights
Interleukin-34 (IL-34) and Macrophage Colony-Stimulating Factor (M-CSF) activate Fms signaling differently. While both support macrophage survival, they diverge in activating specific cellular responses and signaling pathways.
Area of Science:
- Immunology
- Cell Biology
- Molecular Signaling
Background:
- Macrophage Colony-Stimulating Factor (M-CSF) is a key regulator of macrophage production, survival, and function via its receptor, Fms.
- Interleukin-34 (IL-34), a newly identified Fms ligand, shares no sequence homology with M-CSF, raising questions about their functional similarities and differences.
Purpose of the Study:
- To investigate and compare the biological activities and signal activation profiles of IL-34 and M-CSF.
- To elucidate the distinct mechanisms by which IL-34 and M-CSF interact with Fms and influence macrophage behavior.
Main Methods:
- Comparative analysis of IL-34 and M-CSF in cell culture systems using primary macrophages, TF-1-fms cells, and J774A.1 cells.
- Assessment of cell growth, survival, chemokine production (MCP-1, eotaxin-2), morphological changes, and cell migration.
- Analysis of Fms receptor tyrosine phosphorylation, downstream signaling, and receptor downregulation kinetics.
- Utilized anti-Fms monoclonal antibodies to probe ligand-receptor binding interactions.
Main Results:
- Both IL-34 and M-CSF equivalently supported cell growth and survival.
- Significant differences were observed in their ability to induce chemokine production, morphological changes, and cell migration.
- IL-34 induced stronger, transient Fms phosphorylation and faster receptor downregulation compared to M-CSF.
- Distinct binding interactions with Fms were suggested by differential blocking patterns with anti-Fms antibodies.
Conclusions:
- IL-34 and M-CSF, despite binding to the same receptor (Fms), exhibit distinct structural properties and binding domains.
- These differences lead to differential bioactivities and distinct signal activation kinetics and strengths, impacting macrophage phenotype and function.
- Macrophage regulation can be modulated distinctly even at the level of a single receptor, Fms, by alternative ligands.
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