Type I Interferons Function as Autocrine and Paracrine Factors to Induce Autotaxin in Response to TLR Activation.
Type I Interferons Function as Autocrine and Paracrine Factors to Induce Autotaxin in Response to TLR Activation.
复制标题
I 型干扰素作为自分泌和旁分泌因子发挥作用，诱导自分泌运动因子响应 TLR 激活
DOI：
10.1371/journal.pone.0136629
复制
发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Song J;Guan M;Zhao Z;Zhang J
溶血磷脂酸（LPA）是炎症和免疫中重要的磷脂介质。然而，LPA在炎症反应过程中的调节机制尚不清楚。自分泌运动因子 (ATX) 是从溶血磷脂酰胆碱 (LPC) 产生细胞外 LPA 的关键酶。在本研究中，我们发现 TLR4 配体脂多糖 (LPS)、TLR9 配体 CpG 寡核苷酸和 TLR3 配体聚 (I:C) 分别在单核 THP-1 细胞中诱导 ATX。 TLR 配体诱导的 ATX 被 IFN-β 的中和抗体或 IFNAR1 的敲除所消除，表明 I 型 IFN 自分泌环负责 TLR 激活后的 ATX 诱导。 IFN-β和IFN-α均能够通过JAK-STAT和PI3K-AKT途径诱导ATX表达，但时间依赖性方式不同。 IFN-β对ATX的诱导作用被IFN-γ显着增强，而IFN-γ单独对ATX表达没有显着影响，表明I型和II型IFN在ATX诱导中存在协同作用。当 THP-1 细胞用 IFN-α/β 或 TLR 配体处理时，细胞外 LPA 水平显着增加。此外，在用 LPS 或 Poly(I:C) 刺激的人单核细胞衍生的树突状细胞 (moDC) 中发现了 I 型 IFN 介导的 ATX 诱导，并且 IFN-α/β 可以诱导人外周血单核细胞 (PBMC) 和从血液样本中分离的单核细胞中表达 ATX。这些结果表明，响应 TLR 激活，ATX 通过 I 型 INF 自分泌-旁分泌环被诱导，以增强 LPA 的生成。
Lysophosphatidic acid (LPA) is an important phospholipid mediator in inflammation and immunity. However, the mechanism of LPA regulation during inflammatory response is largely unknown. Autotaxin (ATX) is the key enzyme to produce extracellular LPA from lysophosphatidylcholine (LPC). In this study, we found that ATX was induced in monocytic THP-1 cells by TLR4 ligand lipopolysaccharide (LPS), TLR9 ligand CpG oligonucleotide, and TLR3 ligand poly(I:C), respectively. The ATX induction by TLR ligand was abolished by the neutralizing antibody against IFN-β or the knockdown of IFNAR1, indicating that type I IFN autocrine loop is responsible for the ATX induction upon TLR activation. Both IFN-β and IFN-α were able to induce ATX expression via the JAK-STAT and PI3K-AKT pathways but with different time-dependent manners. The ATX induction by IFN-β was dramatically enhanced by IFN-γ, which had no significant effect on ATX expression alone, suggesting a synergy effect between type I and type II IFNs in ATX induction. Extracellular LPA levels were significantly increased when THP-1 cells were treated with IFN-α/β or TLR ligands. In addition, the type I IFN-mediated ATX induction was identified in human monocyte-derived dendritic cells (moDCs) stimulated with LPS or poly(I:C), and IFN-α/β could induce ATX expression in human peripheral blood mononuclear cells (PBMCs) and monocytes isolated form blood samples. These results suggest that, in response to TLR activation, ATX is induced through a type I INF autocrine-paracrine loop to enhance LPA generation.