Laboratory of Molecular Membrane Biology, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland.
J Leukoc Biol. 2019 Dec;106(6):1285-1301. doi: 10.1002/JLB.2A0918-368RR. Epub 2019 Jul 23.
Bacterial LPS strongly induces pro-inflammatory responses of Mϕs after binding to CD14 protein and the TLR4/MD-2 receptor complex. The LPS-triggered signaling can be modulated by extracellular lysophosphatidic acid (LPA), which is of substantial importance for Mϕ functioning under specific pathophysiological conditions, such as atherosclerosis. The molecular mechanisms of the crosstalk between the LPS- and LPA-induced signaling, and the LPA receptors involved, are poorly known. In this report, we show that LPA strongly inhibits the LPS-induced TNF-α production at the mRNA and protein levels in primary Mϕs and Mϕ-like J774 cells. The decreased TNF-α production in LPA/LPS-stimulated cells is to high extent independent of NF-κB but is preceded by enhanced expression and secretion of the anti-inflammatory cytokine IL-10. The IL-10 elevation and TNF-α reduction are both abrogated upon depletion of the LPA and LPA receptors in J774 cells and can be linked with LPA-mediated activation of p38. We propose that the binding of LPA to LPA and LPA fine-tunes the LPS-induced inflammatory response by activating p38, and up-regulating IL-10 and down-regulating TNF-α production.
细菌脂多糖（LPS）与 CD14 蛋白和 TLR4/MD-2 受体复合物结合后，强烈诱导巨噬细胞（Mϕ）产生促炎反应。细胞外溶血磷脂酸（LPA）可以调节 LPS 触发的信号，这对于 Mϕ 在特定病理生理条件下的功能非常重要，例如动脉粥样硬化。LPS 和 LPA 诱导的信号之间的串扰以及涉及的 LPA 受体的分子机制知之甚少。在本报告中，我们表明 LPA 可强烈抑制原代 Mϕ 和 Mϕ 样 J774 细胞中 LPS 诱导的 TNF-α 的 mRNA 和蛋白水平产生。LPA/LPS 刺激细胞中 TNF-α 产生的减少在很大程度上独立于 NF-κB，但伴随着抗炎细胞因子 IL-10 的表达和分泌增强。J774 细胞中 LPA 和 LPA 受体耗竭后，IL-10 升高和 TNF-α 减少均被消除，并且可以与 LPA 介导的 p38 激活相关联。我们提出，LPA 与 LPA 和 LPA 的结合通过激活 p38，上调 IL-10 和下调 TNF-α 的产生，从而精细调节 LPS 诱导的炎症反应。
