Non-steroidal anti-inflammatory drugs increase MRP4 expression in an endometriotic epithelial cell line in a PPARa dependent manner.

Isabella Massimi, Massimi I, I Massimi, Pulcinelli FM, F M Pulcinelli, V P Piscitelli, Piscitelli VP, Vincenzo PISCITELLI, Alemanno L, Laura Alemanno, L Alemanno, Maltese T, Teresa Maltese, T Maltese, Maria Guarino, M L Guarino, Guarino ML, Roberto Marci, R Marci, Marci R, Canny GO, G O Canny, G. Canny, Luigi Frati, Frati L, L Frati, M Mallozzi, Mallozzi M, Maddalena Mallozzi, A Frega, Frega A, Donatella Caserta, D Caserta, Caserta D
European review for medical and pharmacological sciences · 2018 · vol. 22(23) , pp. 8487–8496 · doi:10.26355/eurrev_201812_16549 · PMID:30556891 · W2943471318
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⚙ AI-generated summary by claude@2026-06, 2026-06-09 ⓘ

NSAIDs increase MRP4 mRNA and protein expression in endometriotic cells via a PPARa-dependent mechanism, correlating with increased PGE2 secretion.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-13 · read from full text ⓘ

This paper examined whether aspirin and other NSAIDs increase the expression of the drug transporter MRP4/ABCC4 in a 12Z human endometriotic epithelial cell line, and whether any effect is dependent on the nuclear receptor PPARα. Using Q-RT-PCR and Western blot, the authors found that aspirin and other NSAIDs enhanced both MRP4 mRNA and protein expression, accompanied by increased PPARα expression, and that aspirin- or diclofenac-induced MRP4 upregulation did not occur when PPARα was knocked down by siRNA. They also reported that NSAID-induced MRP4 expression correlated with increased PGE2 secretion, supporting functional relevance of the transporter change. The study is limited to an in vitro epithelial cell line model, and the PPARα-dependent gene regulation was tested specifically in that system. This paper is centrally about endometriosis — it investigates NSAID/aspirin–driven, PPARα-dependent upregulation of MRP4 in an endometriotic epithelial cell line.

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Abstract

OBJECTIVE: Endometriosis is a debilitating disease characterized by chronic inflammation. The transporter multidrug resistance-associated protein 4 (MRP4/ABCC4) is expressed in human endometrial tissue; it is overexpressed in ectopic endometrial tissue, and is modulated by the anti-inflammatory lipid Lipoxin A4 (LXA4). Recently, it was demonstrated that aspirin induces platelet MRP4 over-expression, through genomic modulation in megakaryocytes. Since patients with endometriosis frequently use aspirin or other non-aspirin Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), the aim of this study was to verify whether aspirin and other NSAIDs enhance MRP4 expression in 12Z human endometriotic epithelial cells and whether this was peroxisome proliferator-activated receptor alpha (PPARa) dependent. MATERIALS AND METHODS: MRP4 and PPARa expression was analyzed by Q-RT-PCR using TaqMan® Master Mix and TaqMan® Assay Reagents (Life Technologies, Monza, Italy) and Western blot. RESULTS: In 12Z cells, aspirin and other NSAIDs enhanced MRP4 mRNA and protein expression; these treatments also induced PPARa expression. Aspirin and diclofenac-induced increases in MRP4 expression were not observed in cells where PPARa was knocked down using siRNA. NSAIDs-induced MRP4 expression was correlated with augmented PGE2 secretion, indicating functional relevance. CONCLUSIONS: MRP4 expression was increased in cells treated with NSAIDs and the nuclear receptor PPARa is involved. Elevated PGE2 levels in cell supernatants correlate with its increased transport by MRP4 after NSAID treatment. More importantly, we provide evidence that in endometriotic epithelial cells aspirin and non-aspirin NSAIDs treatments alter gene expression.
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Objective

Endometriosis is a debilitating disease characterized by chronic inflammation. The transporter multidrug resistance-associated protein 4 (MRP4/ABCC4) is expressed in human endometrial tissue; it is overexpressed in ectopic endometrial tissue, and is modulated by the anti-inflammatory lipid Lipoxin A4 (LXA4). Recently, it was demonstrated that aspirin induces platelet MRP4 over-expression, through genomic modulation in megakaryocytes. Since patients with endometriosis frequently use aspirin or other non-aspirin Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), the aim of this study was to verify whether aspirin and other NSAIDs enhance MRP4 expression in 12Z human endometriotic epithelial cells and whether this was peroxisome proliferator-activated receptor alpha (PPARa) dependent.

Materials and methods

MRP4 and PPARa expression was analyzed by Q-RT-PCR using TaqMan® Master Mix and TaqMan® Assay Reagents (Life Technologies, Monza, Italy) and Western blot.

Results

In 12Z cells, aspirin and other NSAIDs enhanced MRP4 mRNA and protein expression; these treatments also induced PPARa expression. Aspirin and diclofenac-induced increases in MRP4 expression were not observed in cells where PPARa was knocked down using siRNA. NSAIDs-induced MRP4 expression was correlated with augmented PGE2 secretion, indicating functional relevance.

Conclusions

MRP4 expression was increased in cells treated with NSAIDs and the nuclear receptor PPARa is involved. Elevated PGE2 levels in cell supernatants correlate with its increased transport by MRP4 after NSAID treatment. More importantly, we provide evidence that in endometriotic epithelial cells aspirin and non-aspirin NSAIDs treatments alter gene expression. Free PDF DownloadThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License To cite this article I. Massimi, F.M. Pulcinelli, V.P. Piscitelli, L. Alemanno, T. Maltese, M.L. Guarino, R. Marci, G.O. Canny, L. Frati, M. Mallozzi, A. Frega, D. Caserta Non-steroidal anti-inflammatory drugs increase MRP4 expression in an endometriotic epithelial cell line in a PPARa dependent manner Eur Rev Med Pharmacol Sci Year: 2018 Vol. 22 - N. 23 Pages: 8487-8496 DOI: 10.26355/eurrev_201812_16549 Publication History Published online: 13 Dec 2018

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Condition tags

endometriosis

MeSH descriptors

Anti-Inflammatory Agents, Non-Steroidal ATP-Binding Cassette, Sub-Family C Proteins Endometriosis PPAR alpha Anti-Inflammatory Agents, Non-Steroidal Aspirin Aspirin ATP-Binding Cassette, Sub-Family C Proteins Cell Line Diclofenac Diclofenac Endometriosis Endometriosis Endometrium Endometrium Epithelial Cells Epithelial Cells Female Humans Italy

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