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 pro-inflammatory arachidonic acid and, in parallel, the glycerophosphoinositols. Here, we investigate the role of the glycerophosphoinositol in inflammatory response. We show that it is part of a negative-feedback loop that limits pro-inflammatory and pro-thrombotic 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 IKKα/β, p38, JNK and Erk1/2 kinases phosphorylation and at the nuclear level with decreased NF-κB translocation and binding to inflammatory gene promoters. In a model of endotoxaemia in the mouse, treatment with glycerophosphoinositol reduced TNF-α synthesis, which supports the concept that glycerophosphoinositol inhibits the de-novo synthesis of pro-inflammatory and pro-thrombotic 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 the manifestations of severe inflammation, by exogenous administration of the compound.