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

Cytokine

PubMedID: 26095744

Ségaliny AI, Brion R, Brulin B, Maillasson M, Charrier C, Téletchéa S, Heymann D. IL-34 and M-CSF form a novel heteromeric cytokine and regulate the M-CSF receptor activation and localization. Cytokine. 2015;.
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.