Integrin engagement regulates monocyte differentiation through the forkhead transcription factor Foxp1.
Integrin engagement regulates monocyte differentiation through the forkhead transcription factor Foxp1.
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整合素参与通过叉头转录因子 Foxp1 调节单核细胞分化。
DOI：
10.1172/jci21100
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发表时间：
2004
期刊：
影响因子：
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通讯作者：
Simon,DanielI
中科院分区：
文献类型：
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作者：
Shi,Can;Zhang,Xiaobin;Chen,Zhiping;Sulaiman,Karina;Feinberg,MarkW;Ballantyne,ChristieM;Jain,MukeshK;Simon,DanielI
血源性单核细胞分化为组织巨噬细胞的确切信号尚未完全确定。整合素的“由外而内”信号传导与影响细胞分化的基因表达调控有关。在这里，我们使用差分显示PCR克隆了一个85 kdaforkhead转录因子（称为mac -1调节叉头[MFH]，随后发现与Foxp1相同），与mac -1聚集的单核THP-1细胞相比，mac -1聚集的β2整合素下调。MFH/ foxp1在未处理的HL60细胞中表达，在佛波酯诱导的单核细胞分化过程中，其表达明显降低，而维甲酸诱导的粒细胞分化过程中则没有。过表达mfh / foxp1显著减弱酚酯诱导的c-fms的表达，而c-fms编码M-CSF受体，是巨噬细胞分化所必需的。同时伴有CD11b表达、细胞粘附性和吞噬作用的降低。通过电迁移转移和报告基因分析，我们已经确定MFH/Foxp1结合到之前未被表征的- fms启动子内的位点，并作为转录抑制因子发挥作用。体内Mac-1的缺乏与mfh / foxp1和单核细胞成熟的调节改变有关。综上所述，这些观察结果表明，Mac-1参与通过调节叉头转录抑制因子mfh /Foxp1的表达来协调单核细胞分化信号。这代表了整合素依赖性基因表达调控和细胞分化调控的新途径。
The precise signals responsible for differentiation of blood-borne monocytes into tissue macrophages are incompletely defined. “Outside-in” signaling by integrins has been implicated in modulation of gene expression that affects cellular differentiation. Herein, using differential display PCR, we have cloned an 85-kDaforkheadtranscription factor (termed Mac-1–regulatedforkhead[MFH] and found subsequently to be identical to Foxp1) that is downregulated in β2-integrin Mac-1–clustered compared with Mac-1–nonclustered monocytic THP-1 cells.MFH/Foxp1is expressed in untreated HL60 cells, and its expression was markedly reduced during phorbol ester–induced monocyte differentiation, but not retinoic acid–induced granulocyte differentiation. Overexpression ofMFH/Foxp1markedly attenuated phorbol ester–induced expression ofc-fms, which encodes the M-CSF receptor and is obligatory for macrophage differentiation. This was accompanied by decreased CD11b expression, cell adhesiveness, and phagocytosis. Using electromobility shift and reporter assays, we have established that MFH/Foxp1 binds to previously uncharacterized sites within thec-fmspromoter and functions as a transcriptional repressor. Deficiency of Mac-1 is associated with altered regulation ofMFH/Foxp1and monocyte maturation in vivo. Taken together, these observations suggest that Mac-1 engagement orchestrates monocyte-differentiation signals by regulating the expression of theforkheadtranscription repressorMFH/Foxp1. This represents a new pathway for integrin-dependent modulation of gene expression and control of cellular differentiation.