IL-34 and M-CSF form a novel heteromeric cytokine and regulate the M-CSF receptor activation and localization
IL-34 and M-CSF form a novel heteromeric cytokine and regulate the M-CSF receptor activation and localization
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DOI：
10.1016/j.cyto.2015.05.029
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发表时间：
2015-12-01
期刊：
影响因子：
3.8
通讯作者：
Heymann, Dominique
中科院分区：
文献类型：
--
作者：
Segaliny, Aude I.;Brion, Regis;Heymann, Dominique
白介素 34 (IL-34) 是一种新发现的同型二聚体细胞因子，与巨噬细胞集落刺激因子 (M-CSF) 一样，通过 M-CSF 受体 (M-CSFR) 信号通路调节骨髓谱系的分化。迄今为止，这两种细胞因子都被认为是 M-CSFR 的竞争性细胞因子。本工作的目的是研究这些细胞因子对表达 M-CSFR 的细胞的功能关系。我们证明，同时添加 M-CSF 和 IL-34 会导致 M-CSFR 出现特定的激活模式，在低浓度下酪氨酸残基会出现较高的磷酸化。类似地，两种细胞因子都对细胞增殖或活力表现出累加效应。此外，BIAcore 实验证明 M-CSF 与 IL-34 结合，分子对接研究预测了异聚 M-CSF/IL-34 细胞因子的形成。邻近连接测定证实了细胞因子之间的这种相互作用。最后，M-CSFR 及其配体的共表达差异调节 M-CSFR 向细胞内的运输。这项研究为理解IL-34和M-CSF之间的功能关系奠定了新的基础，并为开发针对IL-34/M-CSF/M-CSFR轴的治疗方法提供了新的愿景。 (C) 2015 Elsevier Ltd. 保留所有权利。
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. (C) 2015 Elsevier Ltd. All rights reserved.