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Regulation of Phospholipase Isozymes by Nuclear Factor-B in Human Gestational Tissues in Vitro

Department of Obstetrics and Gynaecology, The University of Melbourne and Mercy Perinatal Research Centre, Mercy Hospital for Women, East Melbourne, Victoria, Australia 3002

Address all correspondence and requests for reprints to: Martha Lappas, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, 126 Clarendon Street, East Melbourne, 3002 Victoria, Australia. E-mail: mlappas{at}unimelb.edu.au.

Phospholipid-derived mediators are implicated in the initiation and progression of human labor and delivery, particularly in relation to infection-induced preterm labor. We previously demonstrated that, in human intrauterine tissues, lipopolysaccharide (LPS)-stimulated nuclear factor-B (NF-B) DNA binding activity, and subsequent cytokine release can be suppressed by sulfasalazine (SASP) concentrations greater than 5 mM. The aim of this study was to elucidate the effect the SASP on secretory type II phospholipase A₂ (PLA₂), cytosolic PLA₂ (cPLA₂), cyclooxygenase (COX) isozymes, and subsequent prostaglandin F₂ (PGF₂) production in human gestational tissues. Human placenta, amnion, and choriodecidua (n = 4–9 separate placentas) were incubated in the presence of SASP (0.1, 1, 5, and/or 10 mM) under either basal or LPS (10 µg/ml) conditions. After 6 h incubation, the tissues were collected and assayed for type II PLA₂ by ELISA and cPLA₂, COX-1, and COX-2 content by Western blotting. The incubation medium was collected and assayed for type II PLA₂ and 13,14-dihydro-15-keto PGF₂ release by ELISA and PGF₂ by RIA. Treatment of placenta, amnion, and choriodecidua with SASP concentrations greater than 5 mM significantly inhibited basal and/or LPS-stimulated type II PLA₂ content and release, 13,14-dihydro-15-keto PGF₂ release, and cPLA₂ protein content (ANOVA, P < 0.05); however, no effect of SASP was observed on basal or LPS-stimulated COX-1 or COX-2 protein. Although no effect of SASP was observed on basal and LPS-stimulated PGF₂ release from placenta and amnion, it significantly increased both basal and LPS-stimulated PGF₂ release from choriodecidua. In addition, SASP concentrations of 5 mM or greater significantly suppressed NF-B DNA binding activity. These data are consistent with the hypothesis that NF-B regulates the expression and release of phospholipase isozymes.

This work was supported by the Medical Research Foundation for Women and Babies and National Health and Medical Research Council Grant 114106. M.L. received a Postdoctoral Research Fellowship from the Elizabeth and Vernon Puzey Foundation.

Abbreviations: AP-1, Activator protein-1; COX, cyclooxygenase; cPLA₂, cytosolic PLA₂; IB, inhibitory B; LDH, lactate dehydrogenase; LPS, lipopolysaccharide; NF-B, nuclear factor-B; PGDH, prostaglandin dehydrogenase; PGF₂, prostaglandin F₂; PLA₂, phospholipase A₂; SASP, sulfasalazine.

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