Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine Hannover, Foundation, Hannover, Germany.
College of Veterinary Medicine, Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, NC, USA.
Mol Immunol. 2014 May;59(1):10-8. doi: 10.1016/j.molimm.2013.11.015. Epub 2014 Jan 14.
Sphingosine-1-phosphate (S1P) modulates many cell functions such as lymphocyte trafficking and signaling as well as keratinocyte proliferation. However, less is known about the specific effects of S1P on cytokine production, particularly on the interaction between dendritic cells (DCs) and keratinocytes, cell types which are crucial for the initiation and maintenance of chronic inflammatory skin diseases like atopic dermatitis or psoriasis. Especially the cytokines of the IL-12 family play a dominant role in many inflammatory diseases as they have a significant impact on T-helper cell function. In the present study we show that S1P decreased the production of the pro-inflammatory cytokines IL-12 and IL-23 in LPS-stimulated DCs via the common subunit p40 as well as in the crosstalk with activated keratinocytes. By using specific S1P receptor agonists (SEW2871, FTY720-P) and antagonist (JTE013) we identified an important role for S1P receptor 1 in the modulation of the cytokine profile. While diminishing IL-12 and IL-23 secretion, S1P enhanced IL-27 production in DCs. To elucidate the mechanism of the different impact on the IL-12 family cytokine production, we investigated the mitogen-activated protein kinase (MAPK) and phosphatidylinositide 3-kinase (PI3K) pathways in DCs. By using specific MAPK-Inhibitors (U0126, SB202190, SP600125) we demonstrated that ERK, p38 and JNK differently regulate each pathway of each cytokine. While p38 and JNK did not seem to play a role in the modulation properties of S1P on cytokine production, ERK is at least partially involved in the S1P mediated modulation of IL-12 and IL-27. The PI3K-Inhibitor abrogated the S1P-induced decrease of IL-12 and IL-23 secretion, while it had no influence on the S1P-induced increase of IL-27 production. These data implicate, that S1P has an anti-inflammatory impact on the production of IL-12 family cytokines, indicating therapeutic potential for S1P treatment of several inflammatory diseases like psoriasis.
鞘氨醇-1-磷酸（S1P）调节多种细胞功能，如淋巴细胞迁移和信号转导以及角质形成细胞增殖。然而，对于 S1P 对细胞因子产生的具体影响，特别是对于树突状细胞（DC）和角质形成细胞之间的相互作用，了解较少，这两种细胞类型对于启动和维持特应性皮炎或银屑病等慢性炎症性皮肤病至关重要。特别是白细胞介素-12 家族的细胞因子在许多炎症性疾病中起着主导作用，因为它们对辅助性 T 细胞功能有重大影响。在本研究中，我们表明 S1P 通过共同亚基 p40 降低 LPS 刺激的 DC 中促炎细胞因子 IL-12 和 IL-23 的产生，以及与激活的角质形成细胞的相互作用。通过使用特定的 S1P 受体激动剂（SEW2871、FTY720-P）和拮抗剂（JTE013），我们确定 S1P 受体 1 在调节细胞因子谱方面发挥了重要作用。S1P 降低了 IL-12 和 IL-23 的分泌，同时增强了 DC 中 IL-27 的产生。为了阐明对白细胞介素-12 家族细胞因子产生的不同影响的机制，我们研究了 DC 中的丝裂原活化蛋白激酶（MAPK）和磷脂酰肌醇 3-激酶（PI3K）途径。通过使用特定的 MAPK 抑制剂（U0126、SB202190、SP600125），我们证明 ERK、p38 和 JNK 分别调节每种细胞因子的每条途径。虽然 p38 和 JNK 似乎在 S1P 对细胞因子产生的调节特性中不起作用，但 ERK 至少部分参与了 S1P 介导的 IL-12 和 IL-27 的调节。PI3K 抑制剂消除了 S1P 诱导的 IL-12 和 IL-23 分泌减少，但对 S1P 诱导的 IL-27 产生增加没有影响。这些数据表明，S1P 对白细胞介素-12 家族细胞因子的产生具有抗炎作用，表明 S1P 治疗银屑病等几种炎症性疾病具有治疗潜力。
