Vascular endothelial growth factor (VEGF) is a potent inducer of inflammation, and we have shown that this latter effect is mediated through endothelial cell (EC) PAF synthesis. Since the phospholipid remodelling pathway enzymes (CoA‐independent transacylase, CoA‐IT; phospholipase A2, PLA2; and lyso‐PAF acetyltransferase, lyso‐PAF‐AT) may participate in PAF synthesis, we assessed their contribution to VEGF‐induced PAF synthesis in bovine aortic EC (BAEC) and human umbilical vein EC (HUVEC).

VEGF enhanced BAEC and HUVEC PAF synthesis by up to 28 and 4 fold above basal levels respectively.

A pretreatment with a CoA‐IT and lyso‐PAF‐AT inhibitor (Sanguinarin; 500 nM) blocked VEGF‐induced PAF synthesis by 95%, a specific CoA‐IT inhibitor (SKF45905; 10 – 50 μM) was without effect, confirming the crucial role of the PLA2 and lyso‐PAF‐AT.

Treatment with secreted PLA2 (sPLA2) inhibitors which have been shown to inhibit both groups IIA and V sPLA2 (SB203347; 10 μM and LY311727; 100 μM) blocked EC PAF synthesis by up to 90%, whereas selective inhibition of group IIA sPLA2 (LY311727; 1 μM) had no significant effect.

RT – PCR and Western blot analyses demonstrated the presence of group V sPLA2 whereas group IIA sPLA2 was undetected in EC.

Treatment with cytosolic and calcium‐independent PLA2 inhibitors (Arachidonyl trifluoromethyl ketone, Bromoenol lactone, Methyl arachydonyl fluorophosphate, up to 50 μM) did not prevent but rather potentiated the VEGF effect on EC PAF synthesis.

These results provide evidence that with VEGF activation of EC cells, the group V sPLA2 provides substrate for EC PAF formation.

British Journal of Pharmacology (2001) 134, 197–205; doi:10.1038/sj.bjp.0704215

01 Jul 1999·Prostaglandins & Other Lipid MediatorsQ3 · BIOLOGY

Contribution of Type II PLA2 to prostaglandin formation: A study using a Type II PLA2 specific inhibitor SB 203347

Q3 · BIOLOGY

Article

Author: Rice, G. E. ; King, R. G. ; Munns, M. J.

Arachidonic acid (AA) mobilization by phospholipase A2 (PLA2) and subsequent prostaglandin synthesis is considered to be a pivotal event in inflammation. The purpose of this study was to assess the efficacy of a Type II PLA2 specific inhibitor, SB 203347, in reducing prostaglandin production in Type II PLA2-transfected Chinese hamster ovary (CHO) cells and in human placenta. In both experimental models utilised, Type II PLA2 represents the principal isozyme contributing to total PLA2 enzymatic activity. PLA2 enzymatic activity released into cell culture media and placental explant media was quantified by radiolabelled substrate assay [14C-phosphatidylethanolamine (PE)]. Immunoreactive prostaglandin F2alpha (PGF2alpha) concentrations were determined by radioimmunoassay. SB 203347 (at 0.1-10 microM final concentration) inhibited PLA2 enzymatic activity released by Zn++ -activated CHO cells by up to 60% (P<0.0001). The concentration of PGF2alpha present in culture media was concomitantly reduced by up to 90% (P<0.0001). Similar results were observed for human placental explants. Treatment of human placental explants with SB 203347 (1 microM final concentration) significantly reduced PLA2 enzymatic activity recovered in media after 24 h incubation (P<0.0001; n = 10). Incubation media PGF2alpha concentrations were also reduced by 60% (P<0.00001). The addition of endogenous arachidonic acid (30 microM final concentration) significantly attenuated SB 203347-inhibition of PGF2alpha release (P<0.01). The data obtained in this study are consistent with the hypothesis that Type II PLA2 contributes to the liberation of arachidonic acid for prostanoid formation in human placenta and in cells that abundantly express this isozyme.

01 May 1999·British Journal of PharmacologyQ2 · MEDICINE

Interleukin‐6 production by activated human monocytic cells is enhanced by MK‐571, a specific inhibitor of the multi‐drug resistance protein‐1

Q2 · MEDICINE

Article

Author: Bart-Jan Wierenga ; Michael Müller ; Wim Dokter ; Edo Vellenga ; Leonore Tuyt

The intracellular transport of leukotriene C4 (LTC4) in hematopoietic cells such as human monocytes is controlled by an ATP dependent carrier encoded by the multidrug resistance protein1 (MRP1) gene whose function can be blocked by the compound MK‐571. Since LTs play a major role in control of cytokine expression in monocytes, we questioned whether blocking of the MRP1 mediated function by MK‐571 might affect cytokine production.

MK‐571 strongly enhanced IL‐6 expression at mRNA and protein level in lipopolysaccharide (LPS) and interleukin‐1 (IL‐1) stimulated human monocytes giving rise to 2.0±0.4 (x±s.d.) and 5.7±3.5 fold induction of IL‐6 protein secretion. The increase in IL‐6 secretion was accompanied by an enhanced phosphorylation of p38 but not of c‐Jun‐N terminal kinase.

The involvement of the kinase signalling pathways was further analysed by using SB203580 and PD98059, specific inhibitors of the p38 and ERK1/2 signalling route. MK‐571 mediated upregulation of IL‐6 in the presence of IL‐1 was partially attenuated by SB203580 and PD98059. Electrophoretic mobility shift assays demonstrated that MK‐571 did not affect the IL‐1 induced DNA binding activity of Activator Protein‐1 and Nuclear Factor‐κB but rather enhanced the transactivational activity of an IL‐6 promoter construct. Finally it was shown that the MK‐571 mediated effects on IL‐6 secretion could not be inhibited by the LT synthesis inhibitor SB203347 or by the anti‐oxidant pyrrolidine dithiocarbamate (PDTC).

These results indicate that the membrane transporter MRP1 is involved in the regulation of IL‐6 expression in activated human peripheral blood monocytes.

British Journal of Pharmacology (1999) 127, 441–448; doi:10.1038/sj.bjp.0702577

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