CC chemokine receptor 5 gene promoter activation by the cyclic AMP response element binding transcription factor
CC chemokine receptor 5 gene promoter activation by the cyclic AMP response element binding transcription factor
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DOI：
10.1182/blood-2008-01-135111
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发表时间：
2008-09-01
期刊：
影响因子：
20.3
通讯作者：
van den Elsen, Peter J.
中科院分区：
文献类型：
--
作者：
Kuipers, Hedwich F.;Biesta, Paula J.;van den Elsen, Peter J.
趋化因子受体CCR 5参与多种炎性疾病的发病机制，例如多发性硬化症（MS）、动脉粥样硬化、移植排斥和自身免疫。在以前的研究中，我们已经表明，MS病变的特点是与应激反应相关的转录因子，即IRF-1，NF-κ B B和CREB B-1的表达增强，调节两类主要组织相容性复合体（MHC）分子的表达。MHC-I和MHC-II分子的表达与MS病变中CCR 5的表达有很大重叠。因此，我们研究了这些因子是否也参与了CCR 5的转录调控。使用体外测定，我们确定IRF-1和NF-κ B均不参与CCR 5启动子的激活。这些因子不参与各种细胞类型中内源性CCR 5转录的诱导的发现证实了这一点。相反，我们发现CCR 5的表达受cAMP/CREB通路的调节，并且该通路中的干扰影响内源性CCR 5的转录。由此，我们得出结论，cAMP/CREB途径参与调节CCR 5的转录，并且，鉴于CREB-1蛋白表达的普遍存在性，另外的调节机制必须有助于CCR 5的细胞类型特异性表达。
The chemokine receptor CCR5 is implicated in the pathogenesis of various inflammatory diseases, such as multiple sclerosis (MS), atherosclerosis, transplant rejection, and autoimmunity. In previous studies, we have shown that MS lesions are characterized by enhanced expression of transcription factors associated with stress responses, ie, IRF-1, NF-kappa B, and CREB-1, which modulate expression of both classes of major histocompatibility complex (MHC) molecules. The expression of MHC-1 and MHC-II molecules greatly overlaps with the expression of CCR5 in MS lesions. Therefore, we investigated whether these factors are also involved in the transcriptional regulation of CCR5. Using in vitro assays, we determined that neither IRF-1 nor NF-kappa B is involved in the activation of the CCR5 promoter. This is corroborated by the finding that these factors are not involved in the induction of endogenous CCR5 transcription in various cell types. In contrast, we show that CCR5 expression is regulated by the cAMP/CREB pathway and that interference in this pathway affects endogenous CCR5 transcription. From this, we conclude that the cAMP/CREB pathway is involved in the regulation of CCR5 transcription and that, given the ubiquitous nature of CREB-1 protein expression, additional regulatory mechanisms must contribute to cell type-specific expression of CCR5.