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Lysophosphatidic acid up‐regulates IL‐10 production to inhibit TNF‐α synthesis in Mϕs stimulated with LPS
Author(s) -
Ciesielska Anna,
HromadaJudycka Aneta,
Ziemlińska Ewelina,
Kwiatkowska Katarzyna
Publication year - 2019
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1002/jlb.2a0918-368rr
Subject(s) - lysophosphatidic acid , biology , receptor , microbiology and biotechnology , tlr4 , cytokine , extracellular , cd14 , crosstalk , signal transduction , tumor necrosis factor alpha , secretion , endocrinology , biochemistry , immunology , physics , optics
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 5 and LPA 6 receptors in J774 cells and can be linked with LPA‐mediated activation of p38. We propose that the binding of LPA to LPA 5 and LPA 6 fine‐tunes the LPS‐induced inflammatory response by activating p38, and up‐regulating IL‐10 and down‐regulating TNF‐α production.