The natural phosphoinositide derivative glycerophosphoinositol inhibits the lipopolysaccharide-induced inflammatory and thrombotic responses.

Abstract

Inflammatory responses are elicited through lipid products of phospholipase A2 activity that acts on the membrane phospholipids, including the phosphoinositides, to form the proinflammatory arachidonic acid and, in parallel, the glycerophosphoinositols. Here, we investigate the role of the glycerophosphoinositol in the inflammatory response. We show that it is part of a negative feedback loop that limits proinflammatory and prothrombotic responses in human monocytes stimulated with lipopolysaccharide. This inhibition is exerted both on the signaling cascade initiated by the lipopolysaccharide with the glycerophosphoinositol-dependent decrease in IκB kinase α/β, p38, JNK, and Erk1/2 kinase phosphorylation and at the nuclear level with decreased NF-κB translocation and binding to inflammatory gene promoters. In a model of endotoxemia in the mouse, treatment with glycerophosphoinositol reduced TNF-α synthesis, which supports the concept that glycerophosphoinositol inhibits the de novo synthesis of proinflammatory and prothrombotic compounds and might thus have a role as an endogenous mediator in the resolution of inflammation. As indicated, this effect of glycerophosphoinositol can also be exploited in the treatment of manifestations of severe inflammation by exogenous administration of the compound.

• Authors: Mariangela Vessichelli, Stefania Mariggiò, Alessia Varone, Pasquale Zizza, Angelomaria Di Santo, Concetta Amore, Giuseppe Dell'Elba, Adele Cutignano, Angelo Fontana, Carmela Cacciapuoti, Gaetano Di Costanzo, Mariastella Zannini, Tiziana de Cristofaro, Virgilio Evangelista, Daniela Corda
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 292 Issue 31 Pg. 12828-12841 (08 04 2017) ISSN: 1083-351X [Electronic] United States
• PMID: 28600357 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Anticoagulants
• Biomarkers
• Inositol Phosphates
• Lipopolysaccharides
• NF-kappa B
• glycerylphosphoinositol

Topics

• Active Transport, Cell Nucleus (drug effects)
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology, therapeutic use)
• Anticoagulants (pharmacology, therapeutic use)
• Biomarkers (blood, metabolism)
• Blood Coagulation (drug effects)
• Cells, Cultured
• Chromatin Immunoprecipitation
• Dose-Response Relationship, Drug
• Endotoxemia (drug therapy, immunology, metabolism)
• Gene Expression Regulation (drug effects)
• HeLa Cells
• Humans
• Inositol Phosphates (pharmacology, therapeutic use)
• Lipopolysaccharides (antagonists & inhibitors, toxicity)
• Male
• Mice, Inbred C57BL
• Microscopy, Confocal
• Monocytes (cytology, drug effects, immunology, metabolism)
• NF-kappa B (antagonists & inhibitors, blood, metabolism)
• Phosphorylation (drug effects)
• Protein Processing, Post-Translational (drug effects)