title: IL-34 and M-CSF form a novel heteromeric cytokine and regulate the M-CSF receptor activation and localization.
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.
authors.affiliation: INSERM, UMR 957, Equipe Ligue 2012, Nantes F-44035, France; Université de Nantes, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, France.
authors.forename: Aude I
authors.initials: AI
authors.lastname: Ségaliny
authors.affiliation: INSERM, UMR 957, Equipe Ligue 2012, Nantes F-44035, France; Université de Nantes, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, France; Centre hospitalier universitaire de Nantes, France.
authors.forename: Régis
authors.initials: R
authors.lastname: Brion
authors.affiliation: INSERM, UMR 957, Equipe Ligue 2012, Nantes F-44035, France; Université de Nantes, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, France.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Brulin
authors.affiliation: INSERM, U892, CNRS, U6299, Centre de Recherche en Cancérologie Nantes-Angers, Plateforme IMPACT, SFR Bonamy, Université de Nantes, France.
authors.forename: Mike
authors.initials: M
authors.lastname: Maillasson
authors.affiliation: INSERM, UMR 957, Equipe Ligue 2012, Nantes F-44035, France; Université de Nantes, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Charrier
authors.affiliation: FIP, UMR CNRS 6286, Faculté des Sciences et Techniques, Université de Nantes, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Téletchéa
authors.affiliation: INSERM, UMR 957, Equipe Ligue 2012, Nantes F-44035, France; Université de Nantes, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, France; Centre hospitalier universitaire de Nantes, France. Electronic address: dominique.heymann@univ-nantes.fr.
authors.forename: Dominique
authors.initials: D
authors.lastname: Heymann
mesh_terms: D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D002470:Cell Survival; D016207:Cytokines / Q000737:chemistry / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D007378:Interleukins / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D016173:Macrophage Colony-Stimulating Factor / Q000737:chemistry* / Q000378:metabolism*; D062105:Molecular Docking Simulation; D009000:Monocytes / Q000502:physiology; D010766:Phosphorylation; D055503:Protein Multimerization; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D016207:Cytokines; C529076:IL34 protein, human; D007378:Interleukins; D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor
keywords: Heteromeric cytokine; Interleukin-34; Macrophage-Colony Stimulating Factor; Molecular modeling; cFMS trafficking