Interleukin-1beta and transforming growth factor-beta2 enhance cytosolic high-molecular-mass phospholipase A2 activity and induce prostaglandin E2 formation in rat mesangial cells

The expression of 14 kDa group II phospholipase A2 [also referred to as secretory PLA2 (sPLA2)] is induced in rat glomerular mesangial cells by exposure to inflammatory cytokines and forskolin, a cAMP elevating agent. Previously we have shown that dexamethasone and transforming growth factor-β2 (TGF-β2) suppress sPLA2 protein synthesis and enzyme activity induced by cytokines and forskolin. The regulation of sPLA2 by pro-inflammatory cytokines suggests that the enzyme may play a role in glomerular inflammatory reactions. In order to understand the regulation of sPLA2 in more detail, we investigated whether dexamethasone and TGF-β2 also suppress sPLA2 mRNA after its induction by either interleukin-1β (IL-1β) or forskolin. We found that IL-1β-induced sPLA2 mRNA in rat mesangial cells is not down-regulated by pretreatment of the cells with dexamethasone, even at a concentration of 10 μM, which dramatically decreases sPLA2 protein levels and activity. Metabolic labelling experiments indicated that the decreased sPLA2 levels under these conditions can be explained by inhibition of the rate of sPLA2 synthesis from the elevated mRNA levels. In contrast, the forskolin-induced elevation of sPLA2 mRNA is inhibited by dexamethasone in a concentration-dependent manner. Likewise, TGF-β2 inhibits the elevation of sPLA2 mRNAs induced by either IL-1β or forskolin. The decrease in sPLA2 mRNA caused by TGF-β2 corresponds with the decrease in sPLA2 enzyme levels and activity. These data suggest that cytokine- and forskolin-induced sPLA2 expression is tightly controlled via both transcriptional and post-transcriptional mechanisms. Furthermore, we show that pretreatment of mesangial cells with epidermal growth factor prior to stimulation with IL-1β or forskolin had no suppressing effect on sPLA2 levels or enzyme activity, as has been reported previously for osteoblasts.

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Transforming growth factor β2 differentially modulates interleukin-1 β- and tumour-necrosis-factor-α-stimulated phospholipase A2 and prostaglandin E2 synthesis in rat renal mesangial cells

Biochemical Journal ◽

10.1042/bj2700269 ◽

1990 ◽

Vol 270 (1) ◽

pp. 269-271 ◽

Cited By ~ 31

Author(s):

J Pfeilschifter ◽

W Pignat ◽

J Leighton ◽

F Märki ◽

K Vosbeck ◽

...

Keyword(s):

Growth Factor ◽

Phospholipase A2 ◽

Tumour Necrosis ◽

Transforming Growth Factor ◽

Mesangial Cells ◽

Interleukin 1 ◽

Tnf Alpha ◽

Tgf Beta ◽

Beta 2 ◽

Necrosis Factor

Treatment of rat glomerular mesangial cells with transforming growth factor beta 2 (TGF beta 2) stimulates prostaglandin E2 (PGE2) synthesis. Actinomycin D, cycloheximide and diclofenac attenuate the TGF beta 2-induced PGE2 formation. As shown previously, two proinflammatory cytokines, interleukin 1 beta (IL-1 beta) and tumour necrosis factor alpha (TNF alpha), are potent stimuli for PGE2 and phospholipase A2 secretion from mesangial cells. We report here that, whereas TGF beta 2 potentiates the IL-1 β- and TNF alpha-evoked PGE2 production, it strongly inhibits the phospholipase A2 secretion induced by both cytokines. In addition, the inhibitory effect of TGF beta 2 on phospholipase A2 secretion is not due to the augmented PGE2 formation.

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Epidermal growth factor stimulates phospholipase A2 in vasopressin-treated rat glomerular mesangial cells

Biochemical Journal ◽

10.1042/bj2560469 ◽

1988 ◽

Vol 256 (2) ◽

pp. 469-474 ◽

Cited By ~ 30

Author(s):

B L Margolis ◽

B J Holub ◽

D A Troyer ◽

K L Skorecki

Keyword(s):

Growth Factor ◽

Epidermal Growth Factor ◽

Phospholipase A2 ◽

G Proteins ◽

Mesangial Cells ◽

Ionophore A23187 ◽

Glomerular Mesangial Cells ◽

Epidermal Growth ◽

Arachidonate Release ◽

Phospholipase A2 Activity

Epidermal growth factor (EGF) enhances vasopressin- and ionophore-A23187-induced prostaglandin production and arachidonate release by rat glomerular mesangial cells in culture. The purpose of the present study was to delineate the phospholipid pathways involved in this effect. In cells labelled with [14C]arachidonate, EGF significantly enhanced the free arachidonate released in response to A23187 or vasopressin without enhancing the production of [14C]arachidonate-labelled diacylglycerol. EGF increased the [14C]arachidonate-labelled phosphatidic acid formed in response to vasopressin, but to a much smaller extent than it increased free arachidonate release. These results indicate that activation of phospholipase C is not sufficient to explain the increase in free arachidonate release observed on addition of EGF. To examine if EGF enhanced phospholipase A2 activity, mesangial cells were labelled with [2-2H]glycerol and [14C]-arachidonate, and the formation of arachidonate-poor lysophospholipids was studied. When combined with vasopressin, EGF significantly enhanced the formation of arachidonate-poor lysophospholipids as compared with vasopressin alone. The fate of exogenously added lysophosphatidylcholine was not altered after stimulation with vasopressin plus EGF, indicating that decreased deacylation or reacylation of the lysophospholipids was not responsible for their accumulation. Taken together, these results indicate that EGF enhances free arachidonate release by activation of phospholipase A2. The signalling mechanism responsible for the change in phospholipase A2 activity is not known, but could conceivably involve phosphorylation of modulating proteins such as lipocortin or G-proteins.

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Transforming Growth Factor Alpha Stimulated Phospholipase A2 Activity in Mouse Keratinocytes

Eicosanoids and Other Bioactive Lipids in Cancer, Inflammation and Radiation Injury ◽

10.1007/978-1-4615-3520-1_90 ◽

1993 ◽

pp. 459-462

Author(s):

R. Kast ◽

G. Fürstenberger ◽

F. Marks

Keyword(s):

Growth Factor ◽

Phospholipase A2 ◽

Transforming Growth Factor ◽

Transforming Growth Factor Alpha ◽

Factor Alpha ◽

Mouse Keratinocytes ◽

Phospholipase A2 Activity

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Role of the prostaglandin E2/E-prostanoid 2 receptor signalling pathway in TGFβ-induced mice mesangial cell damage

Bioscience Reports ◽

10.1042/bsr20140130 ◽

2014 ◽

Vol 34 (6) ◽

Cited By ~ 3

Author(s):

Na-Na Li ◽

Yu-Yin Xu ◽

Xiao-Lan Chen ◽

Ya-Ping Fan ◽

Jian-Hua Wu

Keyword(s):

Growth Factor ◽

Prostaglandin E2 ◽

Molecular Mechanisms ◽

Transforming Growth Factor ◽

Mesangial Cells ◽

Tissue Growth ◽

Signalling Pathway ◽

Mitogen Activated Protein Kinase ◽

Type I

The prostaglandin E2 receptor, EP2 (E-prostanoid 2), plays an important role in mice glomerular MCs (mesangial cells) damage induced by TGFβ1 (transforming growth factor-β1); however, the molecular mechanisms for this remain unknown. The present study examined the role of the EP2 signalling pathway in TGFβ1-induced MCs proliferation, ECM (extracellular matrix) accumulation and expression of PGES (prostaglandin E2 synthase). We generated primary mice MCs. Results showed MCs proliferation promoted by TGFβ1 were increased; however, the production of cAMP and PGE2 (prostaglandin E2) was decreased. EP2 deficiency in these MCs augmented FN (fibronectin), Col I (collagen type I), COX2 (cyclooxygenase-2), mPGES-1 (membrane-associated prostaglandin E1), CTGF (connective tissue growth factor) and CyclinD1 expression stimulated by TGFβ1. Silencing of EP2 also strengthened TGFβ1-induced p38MAPK (mitogen-activated protein kinase), ERK1/2 (extracellular-signal-regulated kinase 1/2) and CREB1 (cAMP responsive element-binding protein 1) phosphorylation. In contrast, Adenovirus-mediated EP2 overexpression reversed the effects of EP2-siRNA (small interfering RNA). Collectively, the investigation indicates that EP2 may block p38MAPK, ERK1/2 and CREB1 phosphorylation via activation of cAMP production and stimulation of PGE2 through EP2 receptors which prevent TGFβ1-induced MCs damage. Our findings also suggest that pharmacological targeting of EP2 receptors may provide new inroads to antagonize the damage induced by TGFβ1.

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