Exogenous group II phospholipase A2 induces prostaglandin E2 production in mouse peritoneal macrophages

doi:10.1016/0014-2999(94)90770-6

European Journal of Pharmacology

Volume 253, Issues 1–2, 21 February 1994, Pages 155-161

https://doi.org/10.1016/0014-2999(94)90770-6 Get rights and content

Abstract

Cultures of mouse peritoneal resident macrophages produced prostaglandin E₂ when exposed to extracellular group II phospholipase A₂. The response to group II phospholipase A₂ was concentration dependent, and prostaglandin E₂ production in response to 1 μg/ml purified group II enzyme was comparable to the maximal response elicited by lipopolysaccharide. Group II phospholipase A₂ required millimolar concentrations of extracellular Ca²⁺ for the induction of prostaglandin E₂ production, as well as for phospholipase A₂ activity. YM-26734 (4-(3,5-didodecanoyl-2,4,6-trihydroxyphenyl)-7-hydroxy-2-(4-hydroxyphenyl)chroman), a selective inhibitor of group II phospholipase A₂, inhibited not only the enzyme activity but also the prostaglandin E₂ production-inducing activity of group II phospholipase A₂ in a concentration-dependent manner. These findings suggest that group II phospholipase A₂ released into the extracellular space may induce prostaglandin E₂ production through hydrolysis of plasma membrane phospholipids. Taken together with the previous finding that YM-26734 suppressed inflammatory responses in vivo, these results suggest that group II phospholipase A₂ may play a role in the elicitation and/or progression of inflammatory processes through the production of eicosanoids.

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Cited by (25)

Biological significance of the production of membrane-associated phospholipase A<inf>2</inf> in human gastric cancer
2003, International Congress Series
We examined the immunohistochemical expression of membrane-associated phospholipase A₂ (M-PLA₂), belonging to group II PLA₂, in 44 advanced gastric cancers, using the ABC method and monoclonal antibody anti-human M-PLA₂. M-PLA₂ mRNA was also examined in the same tumors by Northern blot analysis. In addition, the content of M-PLA₂ protein and prostaglandin E₂ (PGE₂) in the malignant lesion and in the non-malignant gastric mucosa was examined. The expression was detected in cancer cells in 31 out of 44 advanced gastric cancer tissues (70.4%) by the ABC method. M-PLA₂ mRNA was detected in 36 out of 44 gastric cancer tissues (81.8%), and the density was observed to be higher in tumor tissues than in the adjacent non-malignant gastric mucosa. The M-PLA₂ protein was detected both in malignant tissues and in non-malignant gastric mucosa, and the content of M-PLA₂ protein was significantly higher in malignant tissues than in the non-malignant gastric mucosa. There was a significant positive correlation between the expression of M-PLA₂ mRNA and the amount of M-PLA₂ protein. PGE₂ was also detected in the malignant tissues and in the non-malignant mucosa. The content of PGE₂ was significantly higher in the former.
These results indicate that M-PLA₂ is produced both in malignant and non-malignant cells of the stomach, the former producing higher amounts of this enzyme than the latter. M-PLA₂ may be involved in cancer progression through its function or through the function of products of this enzyme's action such as PGE₂ in gastric cancer.
Group II phospholipase A2 is increased in peritoneal and pleural effusions in patients with various cancers
2003, International Congress Series
Serum levels of group II phospholipase A2 (PLA2) were reported to be associated with the stage of the disease in cancer patients. These levels are also related to the malignant potential in tissues and are an important prognostic factor. We examined group II PLA2 levels in pleural effusions from patients with various cancers. We also investigated the production of group II PLA2 in cells in effusions from cancer patients. Immunoreactive group II PLA2 levels were significantly higher in effusions from patients with various cancers. There was no significant correlation between group II PLA2 levels in effusions and those in sera. Group II PLA2 mRNA was expressed at a high level in cells from effusions by Northern blot analysis, but not those from blood. The localization of group II PLA2 protein and mRNA was intense in carcinoma cells and CD68 positive macrophages, determined by immunocytochemistry and by in situ hybridization. In addition, IL-6 and IL-8 levels were significantly higher in effusions in comparison with those in sera from the patients (p<0.001), suggesting that cancer cells and macrophages produce group II PLA2 by IL-6. These group II PLA2 levels are apparently significantly increased in effusions, and the carcinoma cells and macrophages produce group II PLA2, as noted in effusions from patients with various cancers.
Dysidotronic acid, a new sesquiterpenoid, inhibits cytokine production and the expression of nitric oxide synthase
2001, European Journal of Pharmacology
In a previous study, we reported a new bioactive sesquiterpenoid, named dysidotronic acid, to be a potent, selective human synovial phospholipase A₂ inhibitor. Dysidotronic acid is a novel, non-complex manoalide analogue lacking the pyranofuranone ring. We now investigate the effect of this compound on cytokine, nitric oxide and prostanoid generation on the mouse macrophage cell line RAW 264.7, where it showed a dose-dependent inhibition with inhibitory concentration 50% values in the micromolar range. This effect was also confirmed in the mouse air pouch injected with zymosan. Dysidotronic acid inhibited the production of tumor necrosis factor alpha and interleukin-1 beta as well as the production of nitric oxide, prostaglandin E₂ and leukotriene B₄. Decreased nitric oxide generation was the consequence of inhibition of the expression of nitric oxide synthase, whereas PGE₂ and LTB₄ reduction was due to inhibition of arachidonic acid bioavailability through a direct inhibitory effect of dysodotronic acid on secretory phospholipase A₂.
Gene expression of group II phospholipase A<inf>2</inf> in intestine in Crohn's disease
1999, American Journal of Gastroenterology
OBJECTIVE:
Phospholipase A₂ (PLA₂) has been suggested to play an important role in the pathogenesis of inflammatory bowel diseases. Our aim was to identify cells that express group II phospholipase A₂ (PLA₂-II) at the mRNA and enzyme protein levels in the intestine in Crohn’s disease.
METHODS:
Tissue samples were obtained from the intestine of 20 patients with Crohn’s disease (seven operated and 13 colonoscopied) and from eight control patients without inflammatory diseases. The samples were studied by immunohistochemistry for PLA₂-II enzyme protein and in situ hybridization for PLA₂-II mRNA.
RESULTS:
PLA₂-II protein and mRNA were detected in the Paneth cells of the small intestinal mucosa in all patients and controls. PLA₂-II protein and mRNA were found in the columnar epithelial cells of the small intestinal mucosa in six of eight and eight of eight patients with Crohn’s ileitis, respectively. In the eight control patients PLA₂-II protein and mRNA were not found in these cells (p = 0.007 and p < 0.001, respectively). Metaplastic Paneth cells, which consistently contained PLA₂-II mRNA, were found in the colonic mucosa in five of six patients with Crohn’s colitis and of one of eight control patients (p = 0.026). The columnar epithelial cells of the colonic mucosa contained PLA₂-II protein in three of six and PLA₂-II mRNA in six of six patients with Crohn’s colitis, whereas the protein was found in these cells in none of eight of the controls (p = 0.055) and the mRNA in only one of eight (p = 0.005) controls.
CONCLUSIONS:
In Crohn’s disease, Paneth cells and columnar epithelial cells of the small and large intestinal mucosa synthesize PLA₂-II at the site of active inflammation.
Surgical trauma induces group II phospholipase A2 production by neutrophils at a local site after surgery
1998, Clinical Biochemistry
Objectives: Group II phospholipase A2 (PLA2) regulates eicosanoids and platelet activating factor (PAF) production and plays an important role in regulating critical mediators in inflammatory diseases such as trauma, sepsis and multiple organ failure. To elucidate the local effect of surgical trauma, we investigated the production of group II PLA2 at a local site after surgery.
Design and methods: We utilized a radioimmunoassay to measure group II PLA2 levels in peritoneal exudates from the operative field and blood in patients who underwent gastrectomy. We also investigated the production of group II PLA2 in cells from peritoneal exudates by Northern blotting and immunocytochemistry.
Results: Immunoreactive group II PLA2 levels were significantly increased from 3 h after surgery and peaked at 12 h in peritoneal exudates. However, serum group II PLA2 levels peaked at 24–48 h and decreased gradually after surgery, findings similar to levels of postoperative serum C-reactive protein (CRP). There was no significant correlation between group II PLA2 levels in peritoneal exudates and those in blood. Group II PLA2 mRNA was expressed at high level in cells from peritoneal exudates, by Northern blot analysis, but not those from blood. The localization of group II PLA2 protein was intense in neutrophils, as determined by immunocytochemistry. No group II PLA2 expression was observed in corresponding peripheral blood cells.
Conclusions: After surgery, group II PLA2 is increased in peritoneal exudates prior to elevation in the blood circulation and is produced by neutrophils recruited and activated at a local site. Group II PLA2 produced in peritoneal exudates by neutrophils has an important role in the physiological and pathological states at a local site, after surgery.
Cross-talk between secretory phospholipase A<inf>2</inf> and cytosolic phospholipase A<inf>2</inf> in rat renal mesangial cells
1997, Biochimica et Biophysica Acta - Lipids and Lipid Metabolism
Incubation of rat glomerular mesangial cells with potent proinflammatory cytokines like interleukin 1β (IL-1β) triggers the expression of a non-pancreatic secretory phospholipase A₂ (sPLA₂) and increases the formation of prostaglandin E₂. We show here that sPLA₂ acts in an autocrine fashion on mesangial cells and induces a rapid activation of protein kinase C (PKC) isoenzymes δ and ϵ and of p42 mitogen-activated protein kinase (MAPK), two putative activators of cytosolic phospholipase A₂ (cPLA₂). sPLA₂ also activates Raf-1 kinase in mesangial cells which integrates the signals coming from PKC for further processing along the MAPK cascade. Subsequently a phosphorylation and activation of cPLA₂ is observed, thus arguing for a cross-talk between the two classes of PLA₂. Pretreatment of cells with either the highly specific PKC inhibitor Ro-318220 or the highly specific MAPK kinase (MEK) inhibitor PD 98059 completely blocked the sPLA₂-induced cPLA₂ activation, indicating that both kinases are essential for the cross-talk between the two types of PLA₂. The effect of sPLA₂ is mimicked by lysophosphatidylcholine (LPC), a reaction product of sPLA₂ activity. LPC stimulates PKC-ϵ, Raf-1 kinase and MAPK activation as well as cPLA₂ activation with a subsequent increase in arachidonic acid release from mesangial cells. These data suggest that sPLA₂ by cleaving membrane phospholipids and generating LPC and other lysophospholipids activates cPLA₂ via the PKC/Raf-1/MAPK signalling pathway. Hence a network of interactions between different PLA₂s is operative in mesangial cells and may contribute to the progression of glomerular inflammatory processes.

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Exogenous group II phospholipase A2 induces prostaglandin E2 production in mouse peritoneal macrophages

Abstract

Biochim. Biophys. Acta

Cell

Biochem. Pharmacol.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

J. Biol. Chem.

FEBS Lett.

Biochim. Biophys. Acta

FEBS Lett.

FEBS Lett.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Exogenous group II phospholipase A₂ induces prostaglandin E₂ production in mouse peritoneal macrophages