IL-34 and M-CSF share the receptor Fms but are not identical in biological activity and signal activation
IL-34 and M-CSF share the receptor Fms but are not identical in biological activity and signal activation
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DOI：
10.1038/cdd.2010.60
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发表时间：
2010-12-01
影响因子：
12.4
通讯作者：
Okada, S.
中科院分区：
文献类型：
--
作者：
Chihara, T.;Suzu, S.;Okada, S.
巨噬细胞集落刺激因子（M-CSF）通过受体酪氨酸激酶Fms调节巨噬细胞的产生、存活和功能。最近，白细胞介素-34（IL-34），其与M-CSF没有序列同源性，被鉴定为替代的Fms配体。在这里，我们提供了第一个证据，这些配体确实相似，但不一定是相同的生物活性和信号激活。在测试的培养系统中，IL-34和M-CSF显示出相同的支持细胞生长或存活的能力。然而，它们在诱导原代巨噬细胞产生趋化因子如MCP-1和eotaxin-2的能力、TF-1-fms细胞的形态学改变和J774A.1细胞的迁移方面存在差异。重要的是，IL-34诱导了更强但短暂的Fms和下游分子的酪氨酸磷酸化，并迅速下调Fms。即使在活性结构域的比较中，这些配体也没有显示出包括半胱氨酸位置在内的序列同源性。有趣的是，抗Fms单克隆抗体（Mab）阻断IL-34-Fms和M-CSF-Fms结合，但另一种Mab仅阻断M-CSF-Fms结合。这些结果表明，IL-34和M-CSF在它们的结构和它们结合的Fms结构域上不同，这导致不同的生物活性和信号激活动力学/强度。我们的研究结果表明，巨噬细胞的表型和功能差异调节，即使在单一受体，Fms的水平。Cell Death and Differentiation（2010）17，1917-1927; doi：10.1038/cdd.2010.60; 2010年5月21日在线发表
Macrophage colony-stimulating factor (M-CSF) regulates the production, survival and function of macrophages through Fms, the receptor tyrosine kinase. Recently, interleukin-34 (IL-34), which shares no sequence homology with M-CSF, was identified as an alternative Fms ligand. Here, we provide the first evidence that these ligands indeed resemble but are not necessarily identical in biological activity and signal activation. In culture systems tested, IL-34 and M-CSF showed an equivalent ability to support cell growth or survival. However, they were different in the ability to induce the production of chemokines such as MCP-1 and eotaxin-2 in primary macrophages, the morphological change in TF-1-fms cells and the migration of J774A.1 cells. Importantly, IL-34 induced a stronger but transient tyrosine phosphorylation of Fms and downstream molecules, and rapidly downregulated Fms. Even in the comparison of active domains, these ligands showed no sequence homology including the position of cysteines. Interestingly, an anti-Fms monoclonal antibody (Mab) blocked both IL-34-Fms and M-CSF-Fms binding, but another MAb blocked only M-CSF-Fms binding. These results suggested that IL-34 and M-CSF differed in their structure and Fms domains that they bound, which caused different bioactivities and signal activation kinetics/strength. Our findings indicate that macrophage phenotype and function are differentially regulated even at the level of the single receptor, Fms. Cell Death and Differentiation (2010) 17, 1917-1927; doi:10.1038/cdd.2010.60; published online 21 May 2010