CCR7-specific migration to CCL19 and CCL21 is induced by PGE2 stimulation in human monocytes: Involvement of EP2/EP4 receptors activation
CCR7-specific migration to CCL19 and CCL21 is induced by PGE2 stimulation in human monocytes: Involvement of EP2/EP4 receptors activation
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DOI：
10.1016/j.molimm.2008.08.269
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发表时间：
2009-08-01
影响因子：
3.6
通讯作者：
Dumais, Nancy
中科院分区：
文献类型：
--
作者：
Cote, Sandra C.;Pasvanis, Stamatoula;Dumais, Nancy
最近的证据表明，新招募的单核细胞不会在炎症部位死亡，而是迁移到引流淋巴结，这一过程中涉及的机制提出了问题。在这项研究中，我们首次证明前列腺素E-2（PGE（2））调节人血液分离的单核细胞以及MONO-MAC-1细胞系中CCR 7的表达和活性。PGE（2）通过与单核细胞上的E-前列腺素2/E-前列腺素4（EP 2/EP 4）受体结合诱导细胞内cAMP形成。在PGE（2）刺激的单核细胞中，向趋化因子CCL 19和CCL 21的迁移是通过增加cAMP浓度介导的，此外，cAMP/PKA途径似乎是MONO-MAC-1中CCR 7转录的主要诱导剂。在PGE（2）诱导p38 MAN表达的同时，我们观察到PGE（2）可下调p42/p44 MAPK磷酸化。在转录水平，抑制p38 MAN抑制CCR 7 mRNA表达。最后，我们证明了转录因子CREB-1和C/EBP α和C/EBP β在PGE（2）刺激后易位到细胞核，并结合有效的CCR 7启动子区域。我们的研究结果可能对HIV-1迁移到淋巴结具有重要意义，因为巨噬细胞和单核细胞，特别是CD 16阳性亚群，对HIV-1感染易感。(C)2008爱思唯尔有限公司保留所有权利。
The recent demonstration that newly recruited monocytes do not die at the site of inflammation, but migrate to draining lymph nodes, raises the question on the mechanism involved in this process. In this study, we demonstrate for the first time that prostaglandin E-2 (PGE(2)) regulates the expression and the activity of CCR7 in human blood-isolated monocytes as well as in the MONO-MAC-1 cell lineage. PGE(2) induces intracellular cAMP formation through engagement of the E-prostanoid 2/E-prostanoid 4 (EP2/EP4) receptors present on monocytes. Migration to chemokines CCL19 and CCL21 in the PGE(2)-stimulated monocytes is mediated through the augmentation of cAMP concentration and furthermore, the cAMP/PKA pathway appears to act as the major inducer of CCR7 transcription in MONO-MAC-1. While p38 MAN was induced by PGE(2), we observed that PGE(2) can downregulate p42/p44 MAPK phosphorylation. At the transcription level, inhibition of p38 MAN inhibits CCR7 mRNA expression. Finally, we demonstrated that transcription factors CREB-1 and C/EBP alpha and C/EBP beta are translocated to the nucleus following PGE(2) stimulation and bind the potent CCR7 promoter region. Our findings may have important implication for HIV-1 migration to the lymph nodes since macrophages and monocytes, particularly CD16 positive subset, are susceptible to HIV-1 infection. (C) 2008 Elsevier Ltd. All rights reserved.