IL-34 and M-CSF form a novel heteromeric cytokine and regulate the M-CSF receptor activation and localization

• Published in: Cytokine (Philadelphia, Pa.) Pa.), 2015-12, Vol.76 (2), p.170-181
• Main Authors: Ségaliny, Aude I., Brion, Régis, Brulin, Bénédicte, Maillasson, Mike, Charrier, Céline, Téletchéa, Stéphane, Heymann, Dominique
• Format: Article
• Language: English
• Subjects: Cell Differentiation; Cell Line, Tumor; Cell Movement - physiology; Cell Proliferation; Cell Survival; cFMS trafficking; Cytokines - chemistry; Cytokines - physiology; HEK293 Cells; Heteromeric cytokine; Humans; Interleukin-34; Interleukins - chemistry; Interleukins - metabolism; Interleukins - pharmacology; Macrophage Colony-Stimulating Factor - chemistry; Macrophage Colony-Stimulating Factor - metabolism; Macrophage-Colony Stimulating Factor; Molecular Docking Simulation; Molecular modeling; Monocytes - physiology; Phosphorylation; Protein Multimerization; Receptor, Macrophage Colony-Stimulating Factor - metabolism; Signal Transduction
• ISSN: 1043-4666; 1096-0023
• DOI: 10.1016/j.cyto.2015.05.029

•IL-34 and M-CSF can interact together to form a heterodimeric cytokine.•Coexpression of the M-CSFR and its ligands regulates M-CSFR trafficking.•M-CSFR glycosylation/localization are regulated by its coexpression with its ligands. Interleukin-34 (IL-34) is a newly-discovered homodimeric cytokine that regulates, like Macrophage Colony-Stimulating Factor (M-CSF), the differentiation of the myeloid lineage through M-CSF receptor (M-CSFR) signaling pathways. To date, both cytokines have been considered as competitive cytokines with regard to the M-CSFR. The aim of the present work was to study the functional relationships of these cytokines on cells expressing the M-CSFR. We demonstrate that simultaneous addition of M-CSF and IL-34 led to a specific activation pattern on the M-CSFR, with higher phosphorylation of the tyrosine residues at low concentrations. Similarly, both cytokines showed an additive effect on cellular proliferation or viability. In addition, BIAcore experiments demonstrated that M-CSF binds to IL-34, and molecular docking studies predicted the formation of a heteromeric M-CSF/IL-34 cytokine. A proximity ligation assay confirmed this interaction between the cytokines. Finally, co-expression of the M-CSFR and its ligands differentially regulated M-CSFR trafficking into the cell. This study establishes a new foundation for the understanding of the functional relationship between IL-34 and M-CSF, and gives a new vision for the development of therapeutic approaches targeting the IL-34/M-CSF/M-CSFR axis.