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

Abstract

Inflammatory responses are elicited through lipid products of phospholipase A 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 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.

Rapid Cerebral Metabolic Shift during Neonatal Sepsis Is Attenuated by Enteral Colostrum Supplementation in Preterm Pigs

“…It has been shown that endogenous metabolites, such as succinate and itaconate, may play separate roles to regulate inflammatory responses [11,12]. In addition, increases in the intracellular glycerophosphoinositol level of macrophages can be observed in lipopolysaccharide-induced inflammation, probably reflecting a modulatory effect on inflammatory responses [13]. Systemic metabolic adaptations during neonatal sepsis have been demonstrated [14] but the effect on cerebral energy metabolism is less known, though it may be of importance.…”

Direct LC-MS/MS Analysis of Extra- and Intracellular Glycerophosphoinositol in Model Cancer Cell Lines

“…For example, it is known that the levels of GroPIns upon transformation or differentiation do not follow the same pattern in all cells, but depend on the active signaling pathways including specific oncogenes or cPLA 2 α activities ( 6 , 7 , 11 , 19 , 29 ). Likewise, it has been shown that GroPIns participates in the resolution of the inflammatory response ( 17 ) and that its release from activated macrophages could induce T cell activation via a paracrine mechanism ( 27 , 34 ). Now it will be possible to mimic these different conditions in vitro and investigate the GroPIns mechanism of action by revealing its dynamic behavior and target/s and shedding light on its putative paracrine role.…”

“…Similarly, treatment of A375MM (human melanoma) and MDA-MB-231 (human mammary carcinoma) cells with GroPIns inhibited their migration in in vitro models of extracellular matrix invasion ( 16 ). Furthermore, GroPIns acted as an anti-inflammatory factor by blocking the signaling cascade triggered by LPS in primary human monocytes, including NF-κB translocation to the nucleus ( 17 ).…”

A signalling cascade involving receptor-activated phospholipase A2, glycerophosphoinositol 4-phosphate, Shp1 and Src in the activation of cell motility

“…Receptors activating the cPLA 2 α/glycerophosphoinositol pathway include adrenergic, purinergic and tyrosine kinase receptors such as epidermal growth factor (EGF) or insulin [3–5]. Also lysophosphatidic-acid receptor in fibroblasts [6], Fc receptor in macrophages [7], lipopolysaccharide-TLR4 in human monocytes [8] lead to glycerophosphoinositol production by activating cPLA 2 α. The glycerophosphoinositol formation is particularly abundant in hematopoietic cells where these compounds are involved in multiple signalling pathways in the context of inflammation and immune reactions [9], generally exerting inhibitory effects [7, 8].…”

“…Also lysophosphatidic-acid receptor in fibroblasts [6], Fc receptor in macrophages [7], lipopolysaccharide-TLR4 in human monocytes [8] lead to glycerophosphoinositol production by activating cPLA 2 α. The glycerophosphoinositol formation is particularly abundant in hematopoietic cells where these compounds are involved in multiple signalling pathways in the context of inflammation and immune reactions [9], generally exerting inhibitory effects [7, 8]. In addition, a major effect of glycerophosphoinositol 4-phosphate (GroPIns4 P ; the phosphorylated form of glycerophosphoinositol, GroPIns) is the regulation of the actin cytoskeleton dynamics in fibroblasts and immune cells [10–12].…”