Lipid Lysophosphatidylcholine Research Articles

Lysophosphatidylcholine: Potential Target for the Treatment of Chronic Pain.

The bioactive lipid lysophosphatidylcholine (LPC), a major phospholipid component of oxidized low-density lipoprotein (Ox-LDL), originates from the cleavage of phosphatidylcholine by phospholipase A2 (PLA2) and is catabolized to other substances by different enzymatic pathways. LPC exerts pleiotropic effects mediated by its receptors, G protein-coupled signaling receptors, Toll-like receptors, and ion channels to activate several second messengers. Lysophosphatidylcholine (LPC) is increasingly considered a key marker/factor positively in pathological states, especially inflammation and atherosclerosis development. Current studies have indicated that the injury of nervous tissues promotes oxidative stress and lipid peroxidation, as well as excessive accumulation of LPC, enhancing the membrane hyperexcitability to induce chronic pain, which may be recognized as one of the hallmarks of chronic pain. However, findings from lipidomic studies of LPC have been lacking in the context of chronic pain. In this review, we focus in some detail on LPC sources, biochemical pathways, and the signal-transduction system. Moreover, we outline the detection methods of LPC for accurate analysis of each individual LPC species and reveal the pathophysiological implication of LPC in chronic pain, which makes it an interesting target for biomarkers and the development of medicine regarding chronic pain.

Procaspase-1 patrolled to the nucleus of proatherogenic lipid LPC-activated human aortic endothelial cells induces ROS promoter CYP1B1 and strong inflammation

To determine the roles of nuclear localization of pro-caspase-1 in human aortic endothelial cells (HAECs) activated by proatherogenic lipid lysophosphatidylcholine (LPC), we examined cytosolic and nuclear localization of pro-caspase-1, identified nuclear export signal (NES) in pro-caspase-1 and sequenced RNAs. We made the following findings: 1) LPC increases nuclear localization of procaspase-1 in HAECs. 2) Nuclear pro-caspase-1 exports back to the cytosol, which is facilitated by a leptomycin B-inhibited mechanism. 3) Increased nuclear localization of pro-caspase-1 by a new NES peptide inhibitor upregulates inflammatory genes in oxidative stress and Th17 pathways; and SUMO activator N106 enhances nuclear localization of pro-caspase-1 and caspase-1 activation (p20) in the nucleus. 4) LPC plus caspase-1 enzymatic inhibitor upregulates inflammatory genes with hypercytokinemia/hyperchemokinemia and interferon pathways, suggesting a novel capsase-1 enzyme-independent inflammatory mechanism. 5) LPC in combination with NES inhibitor and caspase-1 inhibitor upregulate inflammatory gene expression that regulate Th17 activation, endotheli-1 signaling, p38-, and ERK- MAPK pathways. To examine two hallmarks of endothelial activation such as secretomes and membrane protein signaling, LPC plus NES inhibitor upregulate 57 canonical secretomic genes and 76 exosome secretomic genes, respectively, promoting four pathways including Th17, IL-17 promoted cytokines, interferon signaling and cholesterol biosynthesis. LPC with NES inhibitor also promote inflammation via upregulating ROS promoter CYP1B1 and 11 clusters of differentiation (CD) membrane protein pathways. Mechanistically, all the LPC plus NES inhibitor-induced genes are significantly downregulated in CYP1B1-deficient microarray, suggesting that nuclear caspase-1-induced CYP1B1 promotes strong inflammation. These transcriptomic results provide novel insights on the roles of nuclear caspase-1 in sensing DAMPs, inducing ROS promoter CYP1B1 and in regulating a large number of genes that mediate HAEC activation and inflammation. These findings will lead to future development of novel therapeutics for cardiovascular diseases (CVD), inflammations, infections, transplantation, autoimmune disease and cancers. (total words: 284).

Lysophosphatidylcholine promotes intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression in human umbilical vein endothelial cells via an orphan G protein receptor 2-mediated signaling pathway

ABSTRACT The oxLDL-based bioactive lipid lysophosphatidylcholine (LPC) is a key regulator of physiological processes including endothelial cell adhesion marker expression. This study explored the relationship between LPC and the human umbilical vein endothelial cell expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) with a particular focus on the regulation of the LPC-G2A-ICAM-1/VCAM-1 pathway in this context. We explored the LPC-inducible role of orphan G protein receptor 2 (G2A) in associated regulatory processes by using human kidney epithelial (HEK293) cells that had been transfected with pET-G2A, human umbilical vein endothelial cells (HUVECs) in which an shRNA was used to knock down G2A, and western blotting and qPCR assays that were used to confirm changes in gene expression. For in vivo studies, a rabbit model of atherosclerosis was established, with serum biochemistry and histological staining approaches being used to assess pathological outcomes in these animals. The treatment of both HEK293 cells and HUVECs with LPC promoted ICAM-1 and VCAM-1 upregulation, while incubation at a pH of 6.8 suppressed such LPC-induced adhesion marker expression. Knocking down G2A by shRNA and inhibiting NF-κB activity yielded opposite outcomes. The application of a Gi protein inhibitor had no impact on LPC-induced ICAM-1/VCAM-1 expression. Atherosclerotic model exhibited high circulating LDL and LPC levels as well as high aortic wall ICAM-1/VCAM-1 expression. Overall, these results suggested that the LPC-G2A-ICAM-1/VCAM-1 pathway may contribute to the atherogenic activity of oxLDL, with NF-κB antagonists representing potentially viable therapeutic tools for the treatment of cardiovascular disease.

Anti-inflammatory cytokines IL-35 and IL-10 block atherogenic lysophosphatidylcholine-induced, mitochondrial ROS-mediated innate immune activation, but spare innate immune memory signature in endothelial cells

It has been shown that anti-inflammatory cytokines interleukin-35 (IL-35) and IL-10 could inhibit acute endothelial cell (EC) activation, however, it remains unknown if and by what pathways IL-35 and IL-10 could block atherogenic lipid lysophosphatidylcholine (LPC)-induced sustained EC activation; and if mitochondrial reactive oxygen species (mtROS) can differentiate mediation of EC activation from trained immunity (innate immune memory). Using RNA sequencing analyses, biochemical assays, as well as database mining approaches, we compared the effects of IL-35 and IL-10 in LPC-treated human aortic ECs (HAECs). Principal component analysis revealed that both IL-35 and IL-10 could similarly and partially reverse global transcriptome changes induced by LPC. Gene set enrichment analyses showed that while IL-35 and IL-10 could both block acute EC activation, characterized by upregulation of cytokines/chemokines and adhesion molecules, IL-35 is more potent than IL-10 in suppressing innate immune signatures upregulated by LPC. Surprisingly, LPC did not induce the expression of trained tolerance itaconate pathway enzymes but induced trained immunity enzyme expressions; and neither IL-35 nor IL-10 was found to affect LPC-induced trained immunity gene signatures. Mechanistically, IL-35 and IL-10 could suppress mtROS, which partially mediate LPC-induced EC activation and innate immune response. Therefore, anti-inflammatory cytokines could reverse mtROS-mediated acute and innate immune trans-differentiation responses in HAECs, but it could spare metabolic reprogramming and trained immunity signatures, which may not fully depend on mtROS. Our characterizations of anti-inflammatory cytokines in blocking mtROS-mediated acute and prolonged EC activation, and sparing trained immunity are significant for designing novel strategies for treating cardiovascular diseases, other inflammatory diseases, and cancers.

Increasing Upstream Chromatin Long-Range Interactions May Favor Induction of Circular RNAs in LysoPC-Activated Human Aortic Endothelial Cells.

Circular RNAs (circRNAs) are non-coding RNAs that form covalently closed continuous loops, and act as gene regulators in physiological and disease conditions. To test our hypothesis that proatherogenic lipid lysophosphatidylcholine (LPC) induce a set of circRNAs in human aortic endothelial cell (HAEC) activation, we performed circRNA analysis by searching our RNA-Seq data from LPC-activated HAECs, and found: (1) LPC induces significant modulation of 77 newly characterized cirRNAs, among which 47 circRNAs (61%) are upregulated; (2) 34 (72%) out of 47 upregulated circRNAs are upregulated when the corresponding mRNAs are downregulated, suggesting that the majority of circRNAs are upregulated presumably via LPC-induced “abnormal splicing” when the canonical splicing for generation of corresponding mRNAs is suppressed; (3) Upregulation of 47 circRNAs is temporally associated with mRNAs-mediated LPC-upregulated cholesterol synthesis-SREBP2 pathway and LPC-downregulated TGF-β pathway; (4) Increase in upstream chromatin long-range interaction sites to circRNA related genes is associated with preferred circRNA generation over canonical splicing for mRNAs, suggesting that shifting chromatin long-range interaction sites from downstream to upstream may promote induction of a list of circRNAs in lysoPC-activated HAECs; (5) Six significantly changed circRNAs may have sponge functions for miRNAs; and (6) 74% significantly changed circRNAs contain open reading frames, suggesting that putative short proteins may interfere with the protein interaction-based signaling. Our findings have demonstrated for the first time that a new set of LPC-induced circRNAs may contribute to homeostasis in LPC-induced HAEC activation. These novel insights may lead to identifications of new therapeutic targets for treating metabolic cardiovascular diseases, inflammations, and cancers.

Lysophosphatidylcholine promotes trained immunity of human aortic endothelial cells via histone 3 lysine 14 acetylation‐dependent and independent gene modulation

We previously reported that a conditional danger associated molecular pattern (conditional DAMP), pro‐atherogenic lipid lysophosphatidylcholine (lysoPC) induces human aortic endothelial cell (HAEC) activation via histone 3 lysine 14 acetylation (H3K14Ac); and HAEC activation plays important role in vascular inflammation and atherosclerotic cardiovascular diseases. However, the mechanisms underlying how lysoPC induced HAEC activation via histone acetylation remain unknown. To examine this issue, we carried out RNA‐Seq of lysoPC‐treated HAEC; and CHIP‐Seq using antibody to H3K14Ac in lysoPC‐treated HAEC. By analyzing the RNA‐Seq and CHIP‐Seq data, we found out the following results: 1) lysoPC modulates the expressions of 9 out of 31 histone acetyltransferases (HATs) with 6 increased and 3 decreased; and three out of the 6 increased HATs are reported to mediate H3K14Ac; 2) among three Acetyl‐CoA generating enzymes, lysoPC upregulates ACS2 (nucleus) and ACL (cytosol), and decreases ACS1 (peroxisome); 3) lysoPC modulates 5 out of 9 glycolytic enzymes with 3 increased and 2 decreased; and increases 6 out of 7 mevalonate pathway enzymes; 4) lysoPC increases the expressions of both T cell costimulation ligands and receptors; 5) lysoPC‐induced H3K14Ac increases the frequencies of downstream chromatin long range interactions (CLRIs); and lysoPC potentially‐induced other histone acetylations prefer to modulate upstream CLRIs. Our findings have demonstrated that lysoPC promotes HAEC activation and gene modulations via increasing acetylation of H3K14 and potential other histone lysines, and thereby frequencies of chromatin long‐range gene interactions, which significantly enhance newly characterized trained immunity features of HAEC. Our results provide novel therapeutic targets for controlling endothelial cell activation, vascular inflammation, and cardiovascular diseases.Support or Funding InformationThis work was supported by NIH grant to Drs. XF. Yang, H. Wang.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Increasing upstream chromatin long‐range interactions may favor induction of circular RNAs in lysoPC‐activated human aortic endothelial cells

Circular RNAs (circRNAs) are classified as non‐coding RNA that form covalently closed continuous loops and act as gene regulators in physiological and disease conditions. We hypothesize that proatherogenic lipid lysophosphatidylcholine (LPC) induce a set of circRNAs in human aortic endothelial cell (HAEC) activation. We performed circRNA analysis by searching our RNA‐Seq data from LPC‐activated HAECs and found: 1) LPC induce significant modulation of 77 newly characterized cirRNAs, among which 47 circRNAs (61%) are upregulated; 2) 34 (72%) out of 47 upregulated circRNAs are upregulated when the corresponding mRNAs are downregulated, suggesting that the majority of circRNAs are upregulated presumably via LPC‐induced “abnormal splicing” when the canonical splicing for generation of corresponding mRNAs is suppressed; 3) Upregulation of 47 circRNAs is associated with LPC‐upregulated cholesterol synthesis‐SREBP2 pathway and LPC‐downregulated TGF‐β pathway; 4) increased upstream chromatin long‐range interaction sites to circRNA related genes favor circRNA generation over canonical splicing for mRNAs, suggesting that shifting chromatin long‐range interaction sites from downstream to upstream promotes induction of a list of circular RNAs in lysoPC‐activated human aortic endothelial cells; 5) six significantly changed circRNAs may have sponge functions for miRNAs; and 6) 74% significantly changed circRNAs contain open reading frames, suggesting that short proteins may interfere the protein interaction‐based signaling. Our finding have demonstrated for the first time that a new set of LPC‐induced circRNAs may contribute to proatherogenic LPC‐induced HAEC activation. These novel insights may lead to identification of new therapeutic targets for treating metabolic cardiovascular diseases, inflammations and cancers.Support or Funding InformationThis work was supported by NIH grants to Drs. XF Yang and H Wang.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Less Lipid, More Commitment

Sexual differentiation of the malaria parasite is a pre-requisite for transmission from humans to the mosquito vector and has emerged as a target for intervention in eradication efforts. In this issue of Cell, a study from Marti, Clardy, and colleagues (Brancucci etal., 2017) describes a host-derived lipid lysophosphatidylcholine (LysoPC) that regulates sexual commitment.

Lysophosphatidylcholine Regulates Sexual Stage Differentiation in the Human Malaria Parasite Plasmodium falciparum

SummaryTransmission represents a population bottleneck in the Plasmodium life cycle and a key intervention target of ongoing efforts to eradicate malaria. Sexual differentiation is essential for this process, as only sexual parasites, called gametocytes, are infective to the mosquito vector. Gametocyte production rates vary depending on environmental conditions, but external stimuli remain obscure. Here, we show that the host-derived lipid lysophosphatidylcholine (LysoPC) controls P. falciparum cell fate by repressing parasite sexual differentiation. We demonstrate that exogenous LysoPC drives biosynthesis of the essential membrane component phosphatidylcholine. LysoPC restriction induces a compensatory response, linking parasite metabolism to the activation of sexual-stage-specific transcription and gametocyte formation. Our results reveal that malaria parasites can sense and process host-derived physiological signals to regulate differentiation. These data close a critical knowledge gap in parasite biology and introduce a major component of the sexual differentiation pathway in Plasmodium that may provide new approaches for blocking malaria transmission.

Calcium-independent binding of human C-reactive protein to lysophosphatidylcholine in supported planar phospholipid monolayers.

C-reactive protein (CRP), a major acute-phase pentraxin, binds to plasma membranes through the multivalent contacts with zwitterionic phosphorylcholine groups for activating classical complement systems. However, the interaction of CRP with phosphorylcholine-based biomaterials is unknown due to the lack of our understanding on the activation mechanism of CRP in altered local microenvironments. This paper reports the novel calcium-independent interaction of CRP to bioactive phospholipid lysophosphatidylcholine (LPC) in supported phospholipids monolayers as determined using SPR. Binding inhibition experiments indicate exposure of glycerophosphate moiety of LPC is responsible for the calcium-free interaction. Our study may explode the established concept that CRP requires calcium for binding to LPC on damaged cell membranes or biomaterials.

Differential Aortic and Mitral Valve Interstitial Cell Mineralization and the Induction of Mineralization by Lysophosphatidylcholine In Vitro.

Calcific aortic valve disease (CAVD) is a serious condition with vast uncertainty regarding the precise mechanism leading to valve calcification. This study was undertaken to examine the role of the lipid lysophosphatidylcholine (LPC) in a comparison of aortic and mitral valve cellular mineralization. The proportion of LPC in differentially calcified regions of diseased aortic valves was determined using thin layer chromatography (TLC). Next, porcine valvular interstitial cells (pVICs) from the aortic (paVICs) and mitral valve (pmVICs) were cultured with LPC (10-1 - 105 nM) and analyzed for cellular mineralization, alkaline phosphatase activity (ALPa), proliferation, and apoptosis. TLC showed a higher percentage of LPC in calcified regions of tissue compared to non-calcified regions. In pVIC cultures, with the exception of 105 nM LPC, increasing concentrations of LPC led to an increase in phosphate mineralization. Increased levels of calcium content were exhibited at 104 nm LPC application compared to baseline controls. Compared to pmVIC cultures, paVIC cultures had greater total phosphate mineralization, ALPa, calcium content, and apoptosis, under both a baseline control and LPC-treated conditions. This study showed that LPC has the capacity to promote pVIC calcification. Also, paVICs have a greater propensity for mineralization than pmVICs. LPC may be a key factor in the transition of the aortic valve from a healthy to diseased state. In addition, there are intrinsic differences that exist between VICs from different valves that may play a key role in heart valve pathology.

Spatial elucidation of spinal cord lipid- and metabolite- regulations in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating, rapidly progressing disease of the central nervous system that is characterized by motor neuron degeneration in the brain stem and the spinal cord. We employed time of flight secondary ion mass spectrometry (ToF-SIMS) to profile spatial lipid- and metabolite- regulations in post mortem human spinal cord tissue from ALS patients to investigate chemical markers of ALS pathogenesis. ToF-SIMS scans and multivariate analysis of image and spectral data were performed on thoracic human spinal cord sections. Multivariate statistics of the image data allowed delineation of anatomical regions of interest based on their chemical identity. Spectral data extracted from these regions were compared using two different approaches for multivariate statistics, for investigating ALS related lipid and metabolite changes. The results show a significant decrease for cholesterol, triglycerides, and vitamin E in the ventral horn of ALS samples, which is presumably a consequence of motor neuron degeneration. Conversely, the biogenic mediator lipid lysophosphatidylcholine and its fragments were increased in ALS ventral spinal cord, pointing towards neuroinflammatory mechanisms associated with neuronal cell death. ToF-SIMS imaging is a promising approach for chemical histology and pathology for investigating the subcellular mechanisms underlying motor neuron degeneration in amyotrophic lateral sclerosis.

The Outer Surface Lipoprotein VolA Mediates Utilization of Exogenous Lipids by Vibrio cholerae

ABSTRACTPrevious work from our laboratory showed that the Gram-negative aquatic pathogen Vibrio cholerae can take up a much wider repertoire of fatty acids than other Gram-negative organisms. The current work elaborated on the ability of V. cholerae to exploit an even more diverse pool of lipid nutrients from its environment. We have demonstrated that the bacterium can use lysophosphatidylcholine as a metabolite for growth. Using a combination of thin-layer chromatography and mass spectrometry, we also showed that lysophosphatidylcholine-derived fatty acid moieties can be used for remodeling the V. cholerae membrane architecture. Furthermore, we have identified a lysophospholipase, VolA (Vibrio outer membrane lysophospholipase A), required for these activities. The enzyme is well conserved in Vibrio species, is coexpressed with the outer membrane fatty acid transporter FadL, is one of very few surface-exposed lipoprotein enzymes to be identified in Gram-negative bacteria and the first instance of a surface lipoprotein phospholipase. We propose a model whereby the bacterium efficiently couples the liberation of fatty acid from lysophosphatidylcholine to its subsequent metabolic uptake. An expanded ability to scavenge diverse environmental lipids at the bacterial surface increases overall bacterial fitness and promotes homeoviscous adaptation through membrane remodeling.

Sodium dependence of lysophosphatidylcholine-induced caspase-1 activity and reactive oxygen species generation

The proinflammatory cytokines interleukin (IL)-1β and IL-18 play pivotal roles in neuroinflammatory diseases. Caspase-1-mediated proteolytic cleavage is required to convert the premature, biologically inactive cytokines to their biologically active forms capable of promoting tissue inflammation. Although caspases have been recognized as potential therapeutic targets in inflammatory diseases, mechanisms regulating caspase-1 activation are not fully understood. Here we demonstrate that the proinflammatory lipid lysophosphatidylcholine (LPC) initiates microglial caspase-1 activation in a Na +-dependent manner. LPC-induced caspase-1 activity was almost completely inhibited upon omission of extracellular Na +, but was unaffected by inhibition of Na +/K +-ATPase with ouabain or by inhibition of Na +/H + antiport with amiloride. Inhibition of caspase-1-mediated IL-1β processing by Na +-free medium led to reduced amounts of mature IL-1β released from LPC-stimulated microglia. Furthermore, LPC-induced production of reactive oxygen species (ROS) was abolished by Na +-free medium, indicating Na + dependence of NADPH oxidase activity in LPC-stimulated microglia. Since ROS production was found to be crucial to caspase-1 activation in LPC-stimulated microglia, the Na + dependence of caspase-1 can be related to the Na + dependence of NADPH oxidase. In summary, it is suggested that in LPC-activated microglia, Na + influx is required for the production of NADPH oxidase-mediated ROS, which subsequently stimulate caspase-1 activity.

Stimulus-dependent requirement of ion channels for microglial NADPH oxidase-mediated production of reactive oxygen species

Reactive oxygen species (ROS) produced by activated microglial cells play a pivotal role in the pathogenesis of neuro-degenerative and neuro-inflammatory diseases. Here we demonstrate that the pro-inflammatory lipid lysophosphatidylcholine (LPC) is capable of inducing microglial ROS production, which is mediated by the activity of NADPH oxidase. Inhibition of TRPV1 non-selective cation channels abolished ROS production in LPC-stimulated microglia, whereas inhibitors of K + channels, H + channels and Cl − channels had no significant effects. In contrast, activity of all four ion channel types was required for PMA-induced NADPH oxidase-mediated ROS generation, suggesting a differential, stimulus-dependent regulation of microglial ROS production by ion channel activity.

Importance of lipid rafts for lysophosphatidylcholine-induced caspase-1 activation and reactive oxygen species generation

Lipid rafts play an important role in regulating cellular processes and functions. Here, we demonstrate that in microglia stimulated with the pro-inflammatory lipid lysophosphatidylcholine (LPC), caspase-1 activation and NADPH oxidase activity depend on intact lipid rafts. Disruption of lipid rafts with methyl-β-cyclodextrin, fumonisin B1 or nystatin prevented LPC-stimulated caspase-1 activation and reactive oxygen species (ROS) production, whereas LPC-induced Na + influx remained unaffected. Since ROS regulate caspase-1 activity in LPC-stimulated microglia, the effects of lipid raft-disrupting agents on caspase-1 activation can be related to their inhibition of NADPH oxidase-mediated ROS production.

G Protein–Coupled Receptor G2A

See related article, pages 572–580 Atherosclerosis is, in large part, an inflammatory process. White blood cells of different lineages are essential components of the atherosclerotic plaque. More important than their numbers, white blood cells influence the structure of an atherosclerotic plaque, and the function of the vessel in which the plaque is present, by secreting a host of agents that affect resident vascular cells.1 Macrophages, derived from circulating monocytes, are one class of white blood cells that, as part of the atherosclerotic plaque, play a critical part in the progression of the plaque, and in compromising its structural integrity.1 Long before an atherosclerotic plaque is clinically detectable, one of the earliest steps in its genesis is the adhesion of circulating monocytes to the endothelium, and subsequent transmigration into the vessel wall. Because it is well-recognized that these very early stages are critical to plaque development, a great deal of energy has been devoted to trying to understand the mechanisms underpinning them. The work by Hedrick and colleagues in this issue of Circulation Research 2 adds to this understanding. This work examines the part of a G protein–coupled receptor, G2A, in modulating the interaction between monocytes and the vascular endothelium. Using mice that are deficient …

Cell membrane-derived lysophosphatidylcholine activates cardiac ryanodine receptor channels

Lysophosphatidylcholine (LPC) is metabolized from a membrane phospholipid and modulates a variety of channels in the plasma membrane (PM). We examined LPC modulation of cardiac ryanodine receptor (RyR) channels in the sarcoplasmic reticulum (SR) using the planar lipid bilayer method to measure the single-channel currents. Micromolar concentrations of LPC increased the open probability of the reconstituted RyR channels irrespective of whether LPC was added to the cis or trans chamber. LPC also increased the membrane capacitance of the bilayer. The effects of LPC contrasted well with those of sphingosylphosphorylcholine (SPC). Taken together, these results suggest that amphipathic lipid LPC does not bind directly to the RyR channel protein, but rather, is incorporated into the bilayer membrane and activates the channel. Thus, we consider cell membrane-derived LPC to be a putative endogenous mediator that activates not only plasma membrane channels but also RyR channels and induces arrhythmogenic Ca(2+) mobilization in cardiomyocytes.

Human resting CD16–, CD16+ and IL‐2‐, IL‐12‐, IL‐15‐ or IFN‐α‐activated natural killer cells differentially respond to sphingosylphosphorylcholine, lysophosphatidylcholine and platelet‐activating factor

The phosphorylcholine-containing lipid lysophosphatidylcholine (LPC) is abundant in the bloodstream, whereas sphingosylphosphorylcholine (SPC) and platelet-activating factor (PAF) highly accumulate at inflamed sites. Utilizing RT-PCR, flow cytometry and immunoblot analyses, we show for the first time that ovarian cancer G protein-coupled receptor 1, the receptor for SPC, is expressed in IL-2-, IL-12- and IL-15-activated but not in resting CD16-, resting CD16+ or IFN-alpha-activated NK cells. Similarly, G2 accumulation and PAF receptor are variably expressed in these subsets of NK cells. SPC, LPC and PAF differentially induce the chemotaxis of resting and activated NK cells. In the chemotaxis assay, it is observed that resting CD16-CD56bright and CD16+CD56dim cells predominantly respond to LPC, whereas activated NK cells, regardless of the sort of stimulus, robustly respond to PAF. SPC is also a potent chemoattractant for IL-2-, IL-12- and IL-15- but not for IFN-alpha-activated NK cells. Further analysis shows that, depending on the cytokine pattern of NK cell activation, phosphorylcholine-containing lipids differentially affect IFN-gamma secretion by these cells. Our results provide one possible explanation for the tissue compartmentation of NK cells and their ability to secrete IFN-gamma. Furthermore, these results may provide novel information regarding NK cell regulation during inflammation.

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