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Lysophosphatidic acid up-regulates IL-10 production to inhibit TNF- synthesis in Ms stimulated with LPS

Ciesielska, A;Hromada-Judycka, A;Ziemliska, E;Kwiatkowska, K;

Bacterial LPS strongly induces pro-inflammatory responses of Ms 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 M 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- production at the mRNA and protein levels in primary Ms and M-like J774 cells. The decreased TNF- production in LPA/LPS-stimulated cells is to high extent independent of NF-B but is preceded by enhanced expression and secretion of the anti-inflammatory cytokine IL-10. The IL-10 elevation and TNF- reduction are both abrogated upon depletion of the LPA5 and LPA6 receptors in J774 cells and can be linked with LPA-mediated activation of p38. We propose that the binding of LPA to LPA5 and LPA6 fine-tunes the LPS-induced inflammatory response by activating p38, and up-regulating IL-10 and down-regulating TNF- production. 2019 Society for Leukocyte Biology.