Abstract
Pre-eclampsia is a pregnancy-specific disorder characterised by hypertension and proteinuria, which in severe cases results in multi-system disturbances. The maternal syndrome is associated with a pro-inflammatory state, consisting of leukocyte activation, which is thought to contribute to the widespread endothelial dysfunction. We previously showed increased activation of NADPH oxidase in pre-eclampsia, in both neutrophils and B-lymphoblast cell lines (B-LCLs). In this study, the mechanism by which NADPH oxidase activity is increased in pre-eclampsia was further investigated. NADPH oxidase activity was found to be increased in phorbol-12-myristate-13-acetate (PMA) stimulated B-LCLs isolated from women with pre-eclampsia. This correlated with an increase in protein kinase C (PKC) substrate phosphorylation, p47-phox phosphorylation (a regulatory component of NADPH oxidase) and p47-phox directed-kinase activity. Using ion exchange and hydroxyapatite chromatography we identified a major peak of PMA regulated p47-phox kinase activity. Chromatography fractions were probed for PKC isoforms. We found the major peak of p47-phox kinase activity could not be separated from the elution profile of PKC epsilon. Using a peptide inhibitor of PKC epsilon, PMA-induced reactive oxygen species (ROS) production could be reduced to that of a normal B-LCL. These data suggest a pro-inflammatory role for PKC epsilon in the pathogenesis of pre-eclampsia.
Highlights
Pre-eclampsia is a pregnancy-specific disorder and a leading cause of maternal morbidity and perinatal death [1]
We previously showed that PMA-stimulated reactive oxygen species (ROS) production was increased in B-lymphoblast cell lines (B-LCLs) isolated from third trimester and postpartum pre-eclamptic women [10]
There were no significant differences between normal and pre-eclamptic B-LCLs when NADPH oxidase activity was stimulated in this fashion (Figure 1C)
Summary
Pre-eclampsia is a pregnancy-specific disorder and a leading cause of maternal morbidity and perinatal death [1] It is associated with hypertension and proteinuria; its origins are early in gestation, where poor implantation and remodelling of the spiral arteries leads to placental underperfusion and hypoxia. To provide an appropriate response to a specific stimulus, leukocytes may undergo a priming process that enhances ROS production to agonists, such as tumour necrosis factor (TNF) and granulocyte/macrophage colony-stimulating factor (GM-CSF) [6]. This process is largely controlled by kinases, including phosphatidylinositol-3-kinase (PI3K) and p38MAPK. The novel PKC isoform, PKCε, was found to be responsible for this increase and highlights an important role for this kinase in the pathogenesis of pre-eclampsia
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