A novel soluble form of the CSF-1 receptor inhibits proliferation of self-renewing macrophages of goldfish (Carassius auratus L.)
A novel soluble form of the CSF-1 receptor inhibits proliferation of self-renewing macrophages of goldfish (Carassius auratus L.)
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DOI：
10.1016/j.dci.2005.02.006
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发表时间：
2005-01-01
影响因子：
2.9
通讯作者：
Belosevic, M
中科院分区：
文献类型：
--
作者：
Barreda, DR;Hanington, PC;Belosevic, M
巨噬细胞集落刺激因子(CSF-1)是巨噬细胞及其前体细胞存活、增殖和分化的主要调节因子。CSF-1活性通过调节CSF-1及其膜结合受体(CSF-1R)基因表达的机制，以及受体介导的内吞作用、代谢过程和下游信号的抑制而受到严格控制。在此，我们描述了一种控制CSF-1活性的新机制。自养金鱼(Carassius auratus L.)巨噬细胞主动产生一种可溶性形式的CSF-1R(sCSF-1R)，它似乎与膜上的CSF-1R竞争配体结合。SCSF-1R转录本只编码受体的配体结合部分，但通过序列分析确定它来自于一个全长的mRNA物种。基因表达与原代巨噬细胞增殖和分化减少，培养上清液中生长因子活性降低，以及最终导致细胞凋亡的显著表型变化有关。重组sCSF-1R在纳摩尔浓度下可抑制巨噬细胞的增殖。抗重组sCSF-1R的抗体在原代巨噬细胞培养上清液和鱼血清中发现了天然的sCSF-1R，提示存在内源性机制暂时调节sCSF-1R的释放。这是第一个关于可溶性CSF-LR的报道，并指出在离散的自我更新的巨噬细胞群体中，造血控制的内在机制可能在进化过程中是保守的。(C)2005爱思唯尔有限公司。保留所有权利。
Macrophage colony-stimulating factor (CSF-1) is the principal regulator of the survival, proliferation, and differentiation of macrophages and their precursors. CSF-1 activity is tightly controlled through mechanisms regulating gene expression of CSF-1 and its membrane-bound receptor (CSF-1R), as well as by receptor-mediated endocytosis, metabolic processing, and inhibition of downstream signaling. Herein we describe a novel mechanism for control of CSF-1 activity. Spontaneously growing goldfish (Carassius auratus L.) macrophages actively produced a soluble form of CSF-1R (sCSF-1R) that appears to compete for ligand binding with membrane CSF-1R. The sCSF-1R transcript encodes only for the ligand-binding portion of the receptor, but is derived from a full-length mRNA species as determined by sequence analysis. Gene expression was associated with decreased proliferation and differentiation of primary macrophages, decreased growth factor activity in culture supernatants, and marked phenotypic changes that culminated in apoptotic cell death. Recombinant sCSF-1R inhibited macrophage proliferation at nanomolar concentrations. Antibodies against recombinant sCSF-1R identified native sCSF-1R in primary macrophage culture supernatants and fish serum, and suggested the presence of endogenous mechanisms temporally regulating sCSF-1R release. This is the first report of a soluble CSF-lR and points to intrinsic mechanisms of hematopoietic control that may be conserved across evolution in discrete self-renewing macrophage populations. (c) 2005 Elsevier Ltd. All rights reserved.