scholarly journals Bromoenol Lactone, an Inhibitor of Calcium-Independent Phospholipase A2, Suppresses Carrageenan-Induced Prostaglandin Production and Hyperalgesia in Rat Hind Paw

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Keiichiro Tsuchida ◽  
Takae Ibuki ◽  
Kiyoshi Matsumura
Keyword(s):  
Arachidonic Acid ◽  
Radiant Heat ◽  
Prostaglandin E ◽  
Nociceptive Response ◽  
Mrna Levels ◽  
Membrane Phospholipids ◽  
Prostaglandin Production ◽  
Bromoenol Lactone ◽  
Foot Pad ◽  
Calcium Independent Phospholipase A2

Prostaglandin (PG) E2and PGI2are essential to hyperalgesia in inflammatory tissues. These prostaglandins are produced from arachidonic acid, which is cleaved from membrane phospholipids by the action of phospholipase A2(PLA2). Which isozyme of PLA2is responsible for the cleavage of arachidonic acid and the production of prostaglandins essential to inflammation-induced hyperalgesia is not clear. In this study, we examined the effects of two PLA2isozyme-specific inhibitors on carrageenan-induced production of PGE2and PGI2in rat hind paw and behavioral nociceptive response to radiant heat. Local administration of bromoenol lactone (BEL), an inhibitor of calcium-independent PLA2(iPLA2), significantly reduced carrageenan-induced elevation of prostaglandins in the inflamed foot pad 3 h after injection. It also ameliorated the hyperalgesic response between 1 h and 3 h after carrageenan injection. On the other hand, AACOCF3, an inhibitor of cytosolic PLA2, suppressed neither prostaglandin production nor the hyperalgesic response. BEL did not suppress the mRNA levels of iPLA2β, iPLA2γ, cyclooxygenase-2, microsomal prostaglandin E synthase, prostaglandin I synthase, or proinflammatory cytokines in the inflamed foot pad, indicating that BEL did not suppress inflammation itself. These results suggest that iPLA2is involved in the production of prostaglandins and hyperalgesia at the inflammatory loci.

PROSTAGLANDIN PRODUCTION BY INTRA-UTERINE TISSUES FROM PERIPARTURIENT SHEEP: USE OF A SUPERFUSION TECHNIQUE

1978 ◽  
Vol 76 (1) ◽  
pp. 111-121 ◽  
Author(s):  
M. D. MITCHELL ◽  
A. P. F. FLINT
Keyword(s):  
Arachidonic Acid ◽  
Relative Rate ◽  
Prostaglandin E ◽  
Tissue Samples ◽  
Prostaglandin Production ◽  
Small Tissue ◽  
Prostaglandin F

SUMMARY A technique for the continuous superfusion of small tissue samples in vitro has been applied to the study of prostaglandin production by ovine intra-uterine tissues. Basal and oxytocin-stimulated production of prostaglandins was studied at 120–125 days of pregnancy and after dexamethasone-induced delivery. In general, the relative rate of prostaglandin production by tissues was: foetal cotyledon = maternal cotyledon>myometrium and in quantitative order the prostaglandins produced were prostaglandin E (PGE) > prostaglandin F (PGF) = 13,14-dihydro-15-oxo-prostaglandin F (PGFM). Considerable variation was found between the rates of prostaglandin production in individual sheep. Oxytocin had no effect on the production of prostaglandins by tissues obtained before labour but myometrium and maternal cotyledon obtained at delivery exhibited a significant increase in production of PGE and PGF (though not PGFM) in response to oxytocin. Administration of arachidonic acid increased the production of PGE and PGF by the foetal cotyledon.

Parathyroid hormone inhibits Na(+)-K(+)-ATPase through Gq/G11 and the calcium-independent phospholipase A2

1997 ◽  
Vol 272 (6) ◽  
pp. F781-F788 ◽  
Author(s):  
B. H. Derrickson ◽  
L. J. Mandel
Keyword(s):  
Arachidonic Acid ◽  
Parathyroid Hormone ◽  
Phospholipase A2 ◽  
Signaling Pathway ◽  
G Proteins ◽  
Proximal Tubules ◽  
Gtp Binding ◽  
Bromoenol Lactone ◽  
Acid Release ◽  
Calcium Independent Phospholipase A2

Previous studies from this laboratory have demonstrated that the 3–34 analog of parathyroid hormone (PTH) causes a 15–30% inhibition of Na(+)-K(+)-adenosinetriphosphatase (Na(+)-K(+)-ATPase) activity in rat renal proximal tubules through the generation of an increase in intracellular arachidonic acid, followed by its conversion to 20-hydroxyeicosatetraenoic acid (20-HETE) [C. P. Ribeiro and L. J. Mandel. Am. J. Physiol. 262 (Renal Fluid Electrolyte Physiol. 31): F209-F216, 1992; and C. P. Ribeiro, G. Dubay, J. R. Falk, and L. J. Mandel. Am. J. Physiol. 266 (Renal Fluid Electrolyte Physiol. 35): F497-F505, 1994]. The present study also uses proximal tubule suspensions to further elucidate this signaling pathway. Guanosine 5'-O-(2-thiodiphosphate), 500 microM, an inhibitor of heterotrimeric GTP-binding proteins (G proteins), and an anti-Gq/G11 antibody (1:500) both blocked the inhibition of the Na(+)-K(+)-ATPase by PTH-(3–34). Furthermore, a 42-kDa protein was identified in proximal tubules by the anti-Gq/G11 antibody (1:1,000). Bromoenol lactone (BEL), 1 microM, a suicide inhibitor of the calcium-independent 40-kDa phospholipase A2 (PLA2), prevented PTH-(3–34) inhibition of the Na(+)-K(+)-ATPase, unless exogenous 10 microM 20-HETE was added. In addition, BEL blocked the PTH-(3–34)-induced increase in arachidonic acid release in the proximal tubules. We conclude that a member of the Gq family and the calcium-independent 40-kDa PLA2 participate in the PTH-(3–34) signaling pathway in rat proximal tubules by mediating the steps between the binding of PTH-(3–34) to its receptor and the subsequent generation of arachidonic acid.

scholarly journals Selective eicosanoid-generating capacity of cytoplasmic phospholipase A2 in Pseudomonas aeruginosa-infected epithelial cells

2011 ◽  
Vol 300 (2) ◽  
pp. L286-L294 ◽  
Author(s):  
Bryan P. Hurley ◽  
Waheed Pirzai ◽  
Karen L. Mumy ◽  
Karsten Gronert ◽  
Beth A. McCormick
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Arachidonic Acid ◽  
Epithelial Cells ◽  
Phospholipase A ◽  
Prostaglandin E ◽  
Tissue Destruction ◽  
Membrane Phospholipids ◽  
Therapeutic Implications ◽  
Epithelial Barriers ◽  
12 Lipoxygenase

Airway neutrophil infiltration is a pathological hallmark observed in multiple lung diseases including pneumonia and cystic fibrosis. Bacterial pathogens such as Pseudomonas aeruginosa instigate neutrophil recruitment to the air space. Excessive accumulation of neutrophils in the lung often contributes to tissue destruction. Previous studies have unveiled hepoxilin A3 as the key molecular signal driving neutrophils across epithelial barriers. The eicosanoid hepoxilin A3 is a potent neutrophil chemoattractant produced by epithelial cells in response to infection with P. aeruginosa . The enzyme phospholipase A2 liberates arachidonic acid from membrane phospholipids, the rate-limiting step in the synthesis of all eicosanoids, including hepoxilin A3. Once generated, aracidonic acid is acted upon by multiple cyclooxygenases and lipoxygenases producing an array of functionally diverse eicosanoids. Although there are numerous phospholipase A2 isoforms capable of generating arachidonic acid, the isoform most often associated with eicosanoid generation is cytoplasmic phospholipase A2α. In the current study, we observed that the cytoplasmic phospholipase A2α isoform is required for mediating P. aeruginosa -induced production of certain eicosanoids such as prostaglandin E2. However, we found that neutrophil transepithelial migration induced by P. aeruginosa does not require cytoplasmic phospholipase A2α. Furthermore, P. aeruginosa -induced hepoxilin A3 production persists despite cytoplasmic phospholipase A2α suppression and generation of the 12-lipoxygenase metabolite 12-HETE is actually enhanced in this context. These results suggest that alterative phospholipase A2 isoforms are utilized to synthesize 12-lipoxygenase metabolites. The therapeutic implications of these findings are significant when considering anti-inflammatory therapies based on targeting eicosanoid synthesis pathways.

Mass Spectrometric Evidence That Agents That Cause Loss of Ca2+ from Intracellular Compartments Induce Hydrolysis of Arachidonic Acid from Pancreatic Islet Membrane Phospholipids by a Mechanism That Does Not Require a Rise in Cytosolic Ca2+ Concentration**This work was supported by U.S. Public Health Service grants PO1-HL57278, P41-RR-00954, and S10-RR-11260 and by an American Diabetes Association Career Development Award (S.R.).

Endocrinology ◽  
1998 ◽  
Vol 139 (10) ◽  
pp. 4073-4085 ◽  
Author(s):  
William Nowatzke ◽  
Sasanka Ramanadham ◽  
Zhongmin Ma ◽  
Fong-Fu Hsu ◽  
Alan Bohrer ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Ionophore A23187 ◽  
Membrane Phospholipids ◽  
Β Cell ◽  
Phospholipid Hydrolysis ◽  
Intracellular Compartments ◽  
Mass Spectrometric Evidence ◽  
Bromoenol Lactone ◽  
Free Media ◽  
Arachidonate Release

Abstract Stimulation of pancreatic islets with glucose induces phospholipid hydrolysis and accumulation of nonesterified arachidonic acid, which may amplify the glucose-induced Ca2+ entry into isletβ -cells that triggers insulin secretion. Ca2+ loss fromβ -cell intracellular compartments has been proposed to induce both Ca2+ entry and events dependent on arachidonate metabolism. We examine here effects of inducing Ca2+ loss from intracellular sequestration sites with ionophore A23187 and thapsigargin on arachidonate hydrolysis from islet phospholipids. A23187 induces a decline in islet arachidonate-containing phospholipids and release of nonesterified arachidonate. A23187-induced arachidonate release is of similar magnitude when islets are stimulated in Ca2+-replete or in Ca2+-free media or when islets loaded with the intracellular Ca2+ chelator BAPTA are stimulated in Ca2+-free medium, a condition in which A23187 induces no rise in β-cell cytosolic [Ca2+]. Thapsigargin also induces islet arachidonate release under these conditions. A23187- or thapsigargin-induced arachidonate release is prevented by a bromoenol lactone (BEL) inhibitor of a β-cell phospholipase A2 (iPLA2), which does not require Ca2+ for catalytic activity and which is negatively modulated by and physically interacts with calmodulin by Ca2+-dependent mechanisms. Agents that cause Ca2+ loss from islet intracellular compartments thus induce arachidonate hydrolysis from phospholipids by a BEL-sensitive mechanism that does not require a rise in cytosolic [Ca2+], and a BEL-sensitive enzyme-like iPLA2 or a related membranous activity may participate in sensing Ca2+ compartment content.

Phospholipase A2 Enzymes Regulate αIIbβ3-mediated, but not FcγRII Receptor-mediated, pp125FAK Phosphorylation in Platelets

1999 ◽  
Vol 81 (04) ◽  
pp. 618-624 ◽  
Author(s):  
Beatrice Haimovich ◽  
Ping Ji ◽  
Ernest Ginalis ◽  
Ruth Kramer ◽  
Ralph Greco
Keyword(s):  
Arachidonic Acid ◽  
Phospholipase A2 ◽  
Platelet Adhesion ◽  
Specific Inhibitor ◽  
Cytosolic Calcium ◽  
Irreversible Inhibitor ◽  
Mobility Shift ◽  
Bromoenol Lactone ◽  
Calcium Independent Phospholipase A2 ◽  
Platelet Spreading

SummaryThe αIIbβ3 integrin and FcγRII receptors mediate, respectively, platelet adhesion and spreading on fibrinogen and immunoglobulin (IgG) coated surfaces. Platelet adhesion to fibrinogen resulted in a partial conversion of the faster to the slower migrating (phosphorylated) form of Ca+2-sensitive cytosolic phospholipase A2 (cPLA2) but failed to trigger arachidonic acid (AA) release. Full mobility shift of cPLA2 and a massive release of AA release were stimulated by platelet adhesion to IgG or addition of thrombin to the fibrinogen adherent platelets. IgG and thrombin induced AA production were blocked by methyl arachidonyl fluorophosphonate (MAFP), an irreversible inhibitor of cPLA2 and the Ca+2-independent phospholipase A2 (iPLA2). In contrast, bromoenol lactone (BEL), a specific inhibitor of iPLA2 had no effect on the release of AA. MAFP and BEL prevented pp125FAK phosphorylation and platelet spreading on fibrinogen having no effect on pp125FAK phosphorylation or platelet spreading on immobilized IgG. We conclude that αIIbβ3-mediated pp125FAK phosphorylation and platelet spreading on fibrinogen are regulated by PLA2 enzymes.Abbreviations: cPLA2, cytosolic calcium-dependent phospholipase A2; iPLA2, calcium-independent phospholipase A2; BSA, bovine serum albumin; mAB, monoclonal antibody; MAFP, methyl arachidonyl fluorophosphonate; pp125FAK, focal adhesion kinase; BEL, bromoenol lactone; AA, arachidonic acid.

Interaction between cortisol and arachidonic acid on the secretion of LH from ovine pituitary tissue

1991 ◽  
Vol 131 (1) ◽  
pp. 87-94 ◽  
Author(s):  
A. W. Nangalama ◽  
G. P. Moberg
Keyword(s):  
Arachidonic Acid ◽  
Plasma Membrane ◽  
Suppressive Effect ◽  
Inhibitory Effect ◽  
Adrenal Steroids ◽  
Membrane Phospholipids ◽  
Pituitary Tissue ◽  
Receptor Sites ◽  
Lh Release ◽  
Gonadotrophin Releasing Hormone

ABSTRACT In several species, glucocorticoids act directly on the pituitary gonadotroph to suppress the gonadotrophin-releasing hormone (GnRH)-induced secretion of the gonadotrophins, especially LH. A mechanism for this action of these adrenal steroids has not been established, but it appears that the glucocorticoids influence LH release by acting on one or more post-receptor sites. This study investigated whether glucocorticoids disrupt GnRH-induced LH release by altering the liberation of arachidonic acid from plasma membrane phospholipids, a component of GnRH-induced LH release. Using perifused ovine pituitary tissue, it was established that exposure of gonadotrophs to 1–1000 nmol cortisol/l for 4 h or longer significantly reduced GnRH-stimulated LH release with the maximal inhibitory effect being observed after 6 h of exposure to cortisol. This suppressive effect of cortisol could be reversed by administration of arachidonic acid, which in its own right could stimulate LH release from ovine pituitary tissue. Furthermore, the inhibitory effect of cortisol on GnRH-stimulated LH release could be directly correlated with decreased pituitary responsiveness to GnRH-stimulated arachidonic acid liberation, consistent with our hypothesis that glucocorticoids can suppress GnRH-induced secretion of LH by reducing the amount of arachidonic acid available for the exocytotic response of GnRH. Journal of Endocrinology (1991) 131, 87–94

scholarly journals Acute Nicotine Reduces Brain Arachidonic Acid Signaling in Unanesthetized Rats

2009 ◽  
Vol 29 (3) ◽  
pp. 648-658 ◽  
Author(s):  
Lisa Chang ◽  
Stanley I Rapoport ◽  
Henry N Nguyen ◽  
Dede Greenstein ◽  
Mei Chen ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Brain Regions ◽  
Membrane Phospholipids ◽  
Dose Equivalent ◽  
Central Effects ◽  
Postsynaptic Receptors ◽  
Cytosolic Phospholipase ◽  
Presynaptic Release

Nicotine exerts its central effects by activating pre- and postsynaptic nicotinic acetylcholine receptors (nAChRs). Presynaptic nAChRs modulate the release of many neurotransmitters that bind to postsynaptic receptors. These may be coupled to the activation of cytosolic phospholipase A2 (cPLA2), which hydrolyzes arachidonic acid (AA) from membrane phospholipids. We hypothesized that nicotine would modify brain signaling involving AA by binding to nAChRs. Nicotine (0.1 mg/kg, subcutaneously) or saline was injected 2 or 10 mins before infusing [1-14C]AA in unanesthetized rats. The AA incorporation coefficient k∗ (a marker of the AA signal) was measured in 80 brain regions by quantitative autoradiography. Nicotine, compared to saline, when administrated 2 mins before [1-14C]AA infusion, significantly decreased k∗ for AA in 26 regions, including cerebral cortex, thalamus, and habenula—interpeduncular regions, by 13% to 45%. These decreases could be entirely prevented by pretreatment with mecamylamine (1.0 mg/kg, subcutaneously). When administered 10 mins before [1-14C]AA infusion, nicotine did not alter any value of k∗. In summary, nicotine given to unanesthetized rats rapidly reduces signaling involving AA in brain regions containing nAChRs, likely by modulating the presynaptic release of neurotransmitters. The effect shows rapid desensitization and is produced at a nicotine dose equivalent to smoking one cigarette in humans.

scholarly journals Role of arachidonic acid metabolism in transcriptional induction of tumor necrosis factor gene expression by phorbol ester.

1989 ◽  
Vol 9 (1) ◽  
pp. 252-258 ◽  
Author(s):  
J Horiguchi ◽  
D Spriggs ◽  
K Imamura ◽  
R Stone ◽  
R Luebbers ◽  
...  
Keyword(s):  
Gene Expression ◽  
Arachidonic Acid ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Leukotriene B4 ◽  
Mrna Levels ◽  
Arachidonic Acid Release ◽  
Acid Release ◽  
Tnf Gene ◽  
Necrosis Factor

The treatment of human HL-60 promyelocytic leukemia cells with 12-O-tetradecanoylphorbol-13-acetate (TPA) is associated with induction of tumor necrosis factor (TNF) transcript. The study reported here has examined TPA-induced signaling mechanisms responsible for the regulation of TNF gene expression in these cells. Run-on assays demonstrated that TPA increases TNF mRNA levels by transcriptional activation of this gene. The induction of TNF transcripts by TPA was inhibited by the isoquinolinesulfonamide derivative H7 but not by HA1004, suggesting that this effect of TPA is mediated by activation of protein kinase C. TPA treatment also resulted in increased arachidonic acid release. Moreover, inhibitors of phospholipase A2 blocked both the increase in arachidonic acid release and the induction of TNF transcripts. These findings suggest that TPA induces TNF gene expression through the formation of arachidonic acid metabolites. Although indomethacin had no detectable effect on this induction of TNF transcripts, ketoconazole, an inhibitor of 5-lipoxygenase, blocked TPA-induced increases in TNF mRNA levels. Moreover, TNF mRNA levels were increased by the 5-lipoxygenase metabolite leukotriene B4. In contrast, the cyclooxygenase metabolite prostaglandin E2 inhibited the induction of TNF transcripts by TPA. Taken together, these results suggest that TPA induces TNF gene expression through the arachidonic acid cascade and that the level of TNF transcripts is regulated by metabolites of the pathway, leukotriene B4 and prostaglandin E2.

Role of arachidonic acid metabolism in transcriptional induction of tumor necrosis factor gene expression by phorbol ester

1989 ◽  
Vol 9 (1) ◽  
pp. 252-258
Author(s):  
J Horiguchi ◽  
D Spriggs ◽  
K Imamura ◽  
R Stone ◽  
R Luebbers ◽  
...  
Keyword(s):  
Gene Expression ◽  
Arachidonic Acid ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Leukotriene B4 ◽  
Mrna Levels ◽  
Arachidonic Acid Release ◽  
Acid Release ◽  
Tnf Gene ◽  
Necrosis Factor

The treatment of human HL-60 promyelocytic leukemia cells with 12-O-tetradecanoylphorbol-13-acetate (TPA) is associated with induction of tumor necrosis factor (TNF) transcript. The study reported here has examined TPA-induced signaling mechanisms responsible for the regulation of TNF gene expression in these cells. Run-on assays demonstrated that TPA increases TNF mRNA levels by transcriptional activation of this gene. The induction of TNF transcripts by TPA was inhibited by the isoquinolinesulfonamide derivative H7 but not by HA1004, suggesting that this effect of TPA is mediated by activation of protein kinase C. TPA treatment also resulted in increased arachidonic acid release. Moreover, inhibitors of phospholipase A2 blocked both the increase in arachidonic acid release and the induction of TNF transcripts. These findings suggest that TPA induces TNF gene expression through the formation of arachidonic acid metabolites. Although indomethacin had no detectable effect on this induction of TNF transcripts, ketoconazole, an inhibitor of 5-lipoxygenase, blocked TPA-induced increases in TNF mRNA levels. Moreover, TNF mRNA levels were increased by the 5-lipoxygenase metabolite leukotriene B4. In contrast, the cyclooxygenase metabolite prostaglandin E2 inhibited the induction of TNF transcripts by TPA. Taken together, these results suggest that TPA induces TNF gene expression through the arachidonic acid cascade and that the level of TNF transcripts is regulated by metabolites of the pathway, leukotriene B4 and prostaglandin E2.

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