Thivierge Maryse, Stankova Jana, Rola-Pleszczynski Marek
Immunology Division, Department of Pediatrics, Faculty of Medicine, Université de Sherbrooke, Quebec, Canada.
J Allergy Clin Immunol. 2006 May;117(5):1155-62. doi: 10.1016/j.jaci.2005.12.1342. Epub 2006 Feb 21.
Dendritic cells (DCs) acquire, during their maturation, the expression of the chemokine receptor CCR7 and the ability to migrate to lymph nodes in response to CC chemokine ligand 19 (CCL19). This migration is impaired in mice lacking the leukotriene (LT) C4 transporter and restored by addition of exogenous LTC4.
To define the role of LT in human DC function, we studied the expression and function of the cysteinyl-leukotriene (CysLT) receptors during DC differentiation from monocytes and subsequent maturation.
Receptor expression was measured by flow cytometry and real-time PCR. Responsiveness to LTD4 stimulation was assessed by calcium flux and chemotaxis.
Maturation of DC with LPS, a classic Toll-like receptor 4 agonist, reduced CysLT receptor 1 (CysLT1) expression by 50%, whereas CysLT receptor 2 expression was increased. In contrast, the Toll-like receptor 3 agonist poly inosinic and cytidylic acid (polyI:C) had no effect on receptor expression. Downregulation of CysLT1 expression by LPS could not be mimicked by TNF-alpha alone or in combination with IL-1beta or IL-6. It was, however, prevented by inhibitors of COX and could be reproduced by a combination of TNF-alpha and prostaglandin E2. Immature DCs and DCs matured with polyI:C, but not with LPS, responded to LTD4 with a robust cytosolic calcium flux, which was prevented by the CysLT1 antagonist montelukast. LTD4 induced DC chemotaxis and enhanced DC migration in response to CCL19 in DCs matured with polyI:C, but only weakly in DCs matured with LPS.
Our data suggest that human DCs may differentially respond to leukotriene, depending on their maturational stimuli.
Our study demonstrates that some microbial agents can reduce the migration of dendritic cells in response to leukotrienes, with potential for differential involvement of these cells in allergic inflammation.
树突状细胞（DCs）在成熟过程中会获得趋化因子受体CCR7的表达，并具备响应CC趋化因子配体19（CCL19）迁移至淋巴结的能力。在缺乏白三烯（LT）C4转运体的小鼠中，这种迁移功能受损，而添加外源性LTC4可使其恢复。
为明确LT在人类DC功能中的作用，我们研究了半胱氨酰白三烯（CysLT）受体在单核细胞分化为DC及随后成熟过程中的表达和功能。
通过流式细胞术和实时PCR检测受体表达。通过钙流和趋化性评估对LTD4刺激的反应性。
用经典的Toll样受体4激动剂脂多糖（LPS）使DC成熟，可使半胱氨酰白三烯受体1（CysLT1）表达降低50%，而半胱氨酰白三烯受体2表达增加。相比之下，Toll样受体3激动剂聚肌苷酸和聚胞苷酸（polyI:C）对受体表达无影响。LPS导致的CysLT1表达下调不能由单独的肿瘤坏死因子-α（TNF-α）或与白细胞介素-1β（IL-1β）或白细胞介素-6联合模拟。然而，环氧化酶抑制剂可阻止这种下调，且TNF-α与前列腺素E2联合可重现这种现象。未成熟DC和用polyI:C而非LPS使其成熟的DC对LTD4有强烈的胞质钙流反应，半胱氨酰白三烯受体1拮抗剂孟鲁司特可阻止这种反应。LTD4诱导用polyI:C使其成熟的DC趋化，并增强其对CCL19的迁移能力，但在用LPS使其成熟的DC中作用较弱。
我们的数据表明，人类DC可能根据其成熟刺激因素对白三烯产生不同反应。
我们的研究表明，一些微生物制剂可降低树突状细胞对白三烯的迁移反应，这些细胞可能在过敏性炎症中存在不同程度的参与。
