IL-34 and M-CSF form a novel heteromeric cytokine and regulate the M-CSF receptor activation and localization. Issue 2 (December 2015)

• Record Type: Journal Article
• Authors: Ségaliny, Aude I.; Brion, Régis; Brulin, Bénédicte; Maillasson, Mike; Charrier, Céline; Téletchéa, Stéphane; Heymann, Dominique
• Is Part Of: Cytokine. Volume 76:Issue 2(2015)
• Page Start: 170
• Page End: 181
• Publication Date: 2015-12
• Subjects: Interleukin-34 -- Macrophage-Colony Stimulating Factor -- Heteromeric cytokine -- cFMS trafficking -- Molecular modeling; Cytokines -- Periodicals; 571.844
• DOI: 10.1016/j.cyto.2015.05.029
• Languages: English
• ISSNs: 1043-4666

Abstract

Highlights: 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. Abstract: 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.