Targeting cytosolic phospholipase A2 by arachidonyl trifluoromethyl ketone prevents chronic inflammation in mice

Malaviya, Ravi; Ansell, Justin; Hall, L. Mark; Fahmy, Mila; Argentieri, Rochelle L.; Olini, Gilbert C.; Pereira, David; Sur, Runa; Cavender, Druie

doi:10.1016/j.ejphar.2006.03.018

Cited by 30 publications

(23 citation statements)

References 59 publications

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“…This plausible link between C1P generation and inflammation coupled with this study demonstrating that C1P is upstream of cPLA 2 ␣ activation may lead to a much-needed and new generation of therapeutics for inflammatory disorders and cancer. For example, a chemical inhibitor of cPLA 2 ␣ as well as genetic ablation of cPLA 2 ␣ was also shown to prevent the development of airway inflammation in the AHR mouse model of asthma (38). Ablation of the cPLA 2 ␣ gene also significantly reduced pulmonary edema, and cPLA 2 ␣ is also found to be a mediator of acute lung injury induced by sepsis via production of inflammatory mediators, such as eicosanoids (38).…”

Section: Discussionmentioning

confidence: 99%

“…For example, a chemical inhibitor of cPLA 2 ␣ as well as genetic ablation of cPLA 2 ␣ was also shown to prevent the development of airway inflammation in the AHR mouse model of asthma (38). Ablation of the cPLA 2 ␣ gene also significantly reduced pulmonary edema, and cPLA 2 ␣ is also found to be a mediator of acute lung injury induced by sepsis via production of inflammatory mediators, such as eicosanoids (38). In regard to cancer phenotypes, COX-2-derived eicosanoids, such as PGE 2 , contribute to tumorigenesis (39).…”

Section: Discussionmentioning

confidence: 99%

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Ceramide 1-Phosphate Is Required for the Translocation of Group IVA Cytosolic Phospholipase A2 and Prostaglandin Synthesis

Lamour

Subramanian

Wijesinghe

et al. 2009

Journal of Biological Chemistry

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Little is known about the regulation of eicosanoid synthesis proximal to the activation of cytosolic phospholipase A 2 ␣ (cPLA 2 ␣), the initial rate-limiting step. The current view is that cPLA 2 ␣ associates with intracellular/phosphatidylcholine-rich membranes strictly via hydrophobic interactions in response to an increase of intracellular calcium. In opposition to this accepted mechanism of two decades, ceramide 1-phosphate (C1P) has been shown to increase the membrane association of cPLA 2 ␣ in vitro via a novel site in the cationic ␤-groove of the C2 domain (Stahelin, R. V., Subramanian, P., Vora, M., Cho, W., and Chalfant, C. E. In this study we demonstrate that C1P is a proximal and required bioactive lipid for the translocation of cPLA 2 ␣ to intracellular membranes in response to inflammatory agonists (e.g. calcium ionophore and ATP). Last, the absolute requirement of the C1P/ cPLA 2 ␣ interaction was demonstrated for the production of eicosanoids using murine embryonic fibroblasts (cPLA 2 ␣ ؊/؊ ) coupled to "rescue" studies. Therefore, this study provides a paradigm shift in how cPLA 2 ␣ is activated during inflammation.Eicosanoids are a class of bioactive lipids derived from the 20-carbon fatty acid, arachidonic acid (AA), 2 including prostaglandins, prostacyclins, thromboxanes, and leukotrienes. The production of AA is the initial rate-limiting step in the production of eicosanoids, and the major phospholipase that regulates eicosanoids synthesis in response to agonists is group IVA cytosolic phospholipase A 2 (cPLA 2 ␣) (2, 3). Activation of cPLA 2 in cells requires the association of the enzyme with intracellular membranes in a Ca 2ϩ -dependent manner. This translocation of cPLA 2 ␣ from the cytosol to intracellular membranes is mediated by a Ca 2ϩ -dependent lipid binding domain (CaLB domain) located at the N terminus of the enzyme (4 -7). The CaLB domain is ϳ60 amino acids and binds phosphatidylcholine (PC) in a Ca 2ϩ -dependent manner (3, 8 -10). However, it is not known if physiologic calcium is sufficient to activate and translocate cPLA 2 ␣ to membranes in cells or if activation also requires the generation of other activating lipids, such as the focus of this study, ceramide 1-phosphate (C1P).One possible activating lipid, phosphatidylinositol 4,5-diphosphate, was ruled out by Balboa and co-workers (11) as a lipid co-factor required for the translocation of the enzyme. This group showed that the interaction with this lipid (via its catalytic domain) was required for full activity of cPLA 2 ␣ after the enzyme translocated to the membrane (11). Another recent report by Leslie and co-workers (12) confirmed these findings, and a recent study by our laboratory corroborated these findings utilizing biophysical approaches (1). Specifically, we showed that C1P induced a dramatic increase of cPLA 2 ␣ activity strictly by increasing the residence time of cPLA 2 ␣ to membranes, whereas phosphatidylinositol 4,5-diphosphate enhanced the enzymes catalytic activity and membrane penetration (13,14).Recent...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Ceramide 1-Phosphate Is Required for the Translocation of Group IVA Cytosolic Phospholipase A2 and Prostaglandin Synthesis

Lamour

Subramanian

Wijesinghe

et al. 2009

Journal of Biological Chemistry

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“…Furthermore, it was shown that AACOCF3 reduced chronic inflammatory responses in mice; AACOCF3 given i.p. inhibited phorbol ester-induced chronic ear oedema (Malaviya et al, 2006). Oral application of AACOCF3 also prevented the development of airway hyperresponsiveness in a mouse asthma model (Malaviya et al, 2006) and reduced acute lung injury induced by septic syndrome in mice (Nagase et al, 2003).…”

Section: Figurementioning

confidence: 99%

“…inhibited phorbol ester-induced chronic ear oedema (Malaviya et al, 2006). Oral application of AACOCF3 also prevented the development of airway hyperresponsiveness in a mouse asthma model (Malaviya et al, 2006) and reduced acute lung injury induced by septic syndrome in mice (Nagase et al, 2003). AACOCF3 also has beneficial effects in a mouse model of experimental autoimmune encephalomyelitis, which is an inflammatory demyelinating disease of the CNS that results in CNS lesions (Kalyvas and David, 2004).…”

Section: Figurementioning

confidence: 99%

The ω3‐polyunsaturated fatty acid derivatives AVX001 and AVX002 directly inhibit cytosolic phospholipase A₂ and suppress PGE₂ formation in mesangial cells

Huwiler

Feuerherm

Sakem

et al. 2012

British J Pharmacology

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BACKGROUND AND PURPOSEw3-polyunsaturated fatty acids (w3-PUFAs) are known to exert anti-inflammatory effects in various disease models although their direct targets are only poorly characterized. EXPERIMENTAL APPROACHHere we report on two new cPLA2 inhibitors, the w3-derivatives AVX001 and AVX002, and their effects on inflammatory PGE2 production in cultures of renal mesangial cells. KEY RESULTSAVX001 and AVX002 dose-dependently inhibited the group IVA cytosolic phospholipase A2 (cPLA2) in an in vitro activity assay with similar IC50 values for AVX001 and AVX002, whereas the known cPLA2 inhibitor AACOCF3 was less potent and docosahexaenoic acid (DHA) was inactive. In renal mesangial cells, AVX001 and AVX002 suppressed IL-1b-induced PGE2 synthesis. Mechanistically, this effect occurred by a down-regulation of IL-1b-induced group IIA-sPLA2 protein expression, mRNA expression and promoter activity. A similar but less potent effect was seen with AACOCF3 and no effect was seen with DHA. As gene expression of sPLA2 is known to be regulated by the transcription factor NF-kB, we further investigated NF-kB activation. Both compounds prevented NF-kB activation by blocking degradation of the inhibitor of kB. CONCLUSIONS AND IMPLICATIONSThese data show for the first time that the novel cPLA2 inhibitors AVX001 and AVX002 exert an anti-inflammatory effect in cultures of renal mesangial cells and reduce the pro-inflammatory mediator PGE2 through an inhibitory effect on NF-kB activation. Therefore, these compounds may represent promising novel drugs for the treatment of inflammatory disorders. AbbreviationsAACOCF3, ATK, arachidonyl-trifluoromethyl ketone; AVX001, 1-octadeca-2,6,9,12,15-pentaenylsulfanyl-propan-2-one; AVX002, 1-octadeca-3,6,9,12,15-pentaenylsulfanyl-propan-2-one; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; IkB, inhibitor of kB; MAFP, methyl-arachidonyl fluorophosphonate; PAF-AH, PAF acetylhydrolase; PUFA, polyunsaturated fatty acid; RT-PCR, reverse transcriptase-PCR BJP British Journal of Pharmacology DOI:10.1111DOI:10. /j.1476DOI:10. -5381.2012 British Journal of Pharmacology (2012) IntroductionMesangial cells are specialized smooth muscle-like cells located in the renal glomerulus and are not only involved in the regulation of the glomerular filtration rate and in the preservation of the structural integrity of the glomerulus, but also play a central role in most pathological processes of the renal glomerulus (Kashgarian and Sterzel, 1992;Pfeilschifter, 1994;Gómez-Guerrero et al., 2005). Upon activation by a variety of pro-inflammatory cytokines, mesangial cells respond with three prominent reactions which are all hallmarks of many forms of glomerulonephritis: (i) increased proliferation; (ii) increased mediator production, including cytokines, chemokines, NO, superoxide radicals and PGs; and (iii) increased extracellular matrix production (Kashgarian and Sterzel, 1992;Pfeilschifter, 1994). The detailed mechanisms underlying these cellular responses are still not completely understood. One importan...

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“…PLA 2 isoenzymes are not only involved in the generation of free arachidonic acid (AA), which is metabolized by cyclo-and lipoxygenases to eicosanoids (22), but also in the incorporation of free AA into membranes and redistribution into specific compartments (remodeling) (23,24). Besides regulatory functions in lipid catabolism/metabolism, PLA 2 enzymes are critically involved in signal transduction, phospholipid and cell membrane bilayer remodeling (25), store-operated cation channels and Ca 2+ releaseactivated Ca 2+ channels (26), Fas-induced apoptosis (27), cellular proliferation and differentiation (28,29), glucose-induced insulin secretion (30), and, most important for this study, they play a central role in acute (18) and chronic inflammation (31).…”

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Ginger Phenylpropanoids Inhibit IL-1β and Prostanoid Secretion and Disrupt Arachidonate-Phospholipid Remodeling by Targeting Phospholipases A2

Nievergelt

Marazzi

Schoop³

et al. 2011

The Journal of Immunology

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The rhizome of ginger (Zingiber officinale) is employed in Asian traditional medicine to treat mild forms of rheumatoid arthritis and fever. We have profiled ginger constituents for robust effects on proinflammatory signaling and cytokine expression in a validated assay using human whole blood. Independent of the stimulus used (LPS, PMA, anti-CD28 Ab, anti-CD3 Ab, and thapsigargin), ginger constituents potently and specifically inhibited IL-1β expression in monocytes/macrophages. Both the calcium-independent phospholipase A2 (iPLA2)-triggered maturation and the cytosolic phospholipase A2 (cPLA2)-dependent secretion of IL-1β from isolated human monocytes were inhibited. In a fluorescence-coupled PLA2 assay, most major ginger phenylpropanoids directly inhibited i/cPLA2 from U937 macrophages, but not hog pancreas secretory phospholipase A2. The effects of the ginger constituents were additive and the potency comparable to the mechanism-based inhibitor bromoenol lactone for iPLA2 and methyl arachidonyl fluorophosphonate for cPLA2, with 10-gingerol/-shogaol being most effective. Furthermore, a ginger extract (2 μg/ml) and 10-shogaol (2 μM) potently inhibited the release of PGE2 and thromboxane B2 (>50%) and partially also leukotriene B4 in LPS-stimulated macrophages. Intriguingly, the total cellular arachidonic acid was increased 2- to 3-fold in U937 cells under all experimental conditions. Our data show that the concurrent inhibition of iPLA2 and prostanoid production causes an accumulation of free intracellular arachidonic acid by disrupting the phospholipid deacylation-reacylation cycle. The inhibition of i/cPLA2, the resulting attenuation of IL-1β secretion, and the simultaneous inhibition of prostanoid production by common ginger phenylpropanoids uncover a new anti-inflammatory molecular mechanism of dietary ginger that may be exploited therapeutically.

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Targeting cytosolic phospholipase A2 by arachidonyl trifluoromethyl ketone prevents chronic inflammation in mice

Cited by 30 publications

References 59 publications

Ceramide 1-Phosphate Is Required for the Translocation of Group IVA Cytosolic Phospholipase A2 and Prostaglandin Synthesis

Ceramide 1-Phosphate Is Required for the Translocation of Group IVA Cytosolic Phospholipase A2 and Prostaglandin Synthesis

The ω3‐polyunsaturated fatty acid derivatives AVX001 and AVX002 directly inhibit cytosolic phospholipase A₂ and suppress PGE₂ formation in mesangial cells

Ginger Phenylpropanoids Inhibit IL-1β and Prostanoid Secretion and Disrupt Arachidonate-Phospholipid Remodeling by Targeting Phospholipases A2

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Targeting cytosolic phospholipase A2 by arachidonyl trifluoromethyl ketone prevents chronic inflammation in mice

Cited by 30 publications

References 59 publications

Ceramide 1-Phosphate Is Required for the Translocation of Group IVA Cytosolic Phospholipase A2 and Prostaglandin Synthesis

Ceramide 1-Phosphate Is Required for the Translocation of Group IVA Cytosolic Phospholipase A2 and Prostaglandin Synthesis

The ω3‐polyunsaturated fatty acid derivatives AVX001 and AVX002 directly inhibit cytosolic phospholipase A2 and suppress PGE2 formation in mesangial cells

Ginger Phenylpropanoids Inhibit IL-1β and Prostanoid Secretion and Disrupt Arachidonate-Phospholipid Remodeling by Targeting Phospholipases A2

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The ω3‐polyunsaturated fatty acid derivatives AVX001 and AVX002 directly inhibit cytosolic phospholipase A₂ and suppress PGE₂ formation in mesangial cells