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

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

Research output: Contribution to journalArticle

Abstract

OBJECTIVE: Endometriosis is a debilitating disease characterized by chronic inflammation. The transporter multidrug resistanceassociated 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 (PPARα) dependent. MATERIALS AND METHODS: MRP4 and PPARα 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 PPARα expression. Aspirin and diclofenac-induced increases in MRP4 expression were not observed in cells where PPARα 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 PPARα 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.

Original languageEnglish
Pages (from-to)8487-8496
Number of pages10
JournalEuropean Review for Medical and Pharmacological Sciences
Volume22
Issue number23
Publication statusPublished - Jan 1 2018

Fingerprint

PPAR alpha
Anti-Inflammatory Agents
Epithelial Cells
Aspirin
Cell Line
Pharmaceutical Preparations
Endometriosis
Dinoprostone
Drug Receptors
Choristoma
Megakaryocytes
Diclofenac
Cytoplasmic and Nuclear Receptors
Italy
Small Interfering RNA
Proteins
Chronic Disease
Therapeutics
Blood Platelets
Western Blotting

Keywords

  • Aspirin
  • Endometriosis
  • MRP4/ABCC4
  • NSAID
  • Pain

ASJC Scopus subject areas

  • Pharmacology (medical)

Cite this

Massimi, I., Pulcinelli, F. M., Piscitelli, V. P., Alemanno, L., Maltese, T., Guarino, M. L., ... Caserta, D. (2018). Non-steroidal anti-inflammatory drugs increase MRP4 expression in an endometriotic epithelial cell line in a PPARα dependent manner. European Review for Medical and Pharmacological Sciences, 22(23), 8487-8496.

Non-steroidal anti-inflammatory drugs increase MRP4 expression in an endometriotic epithelial cell line in a PPARα dependent manner. / Massimi, I.; Pulcinelli, F. M.; Piscitelli, V. P.; Alemanno, L.; Maltese, T.; Guarino, M. L.; Marci, R.; Canny, G. O.; Frati, L.; Mallozzi, M.; Frega, A.; Caserta, D.

In: European Review for Medical and Pharmacological Sciences, Vol. 22, No. 23, 01.01.2018, p. 8487-8496.

Research output: Contribution to journalArticle

Massimi, I, Pulcinelli, FM, Piscitelli, VP, Alemanno, L, Maltese, T, Guarino, ML, Marci, R, Canny, GO, Frati, L, Mallozzi, M, Frega, A & Caserta, D 2018, 'Non-steroidal anti-inflammatory drugs increase MRP4 expression in an endometriotic epithelial cell line in a PPARα dependent manner', European Review for Medical and Pharmacological Sciences, vol. 22, no. 23, pp. 8487-8496.
Massimi, I. ; Pulcinelli, F. M. ; Piscitelli, V. P. ; Alemanno, L. ; Maltese, T. ; Guarino, M. L. ; Marci, R. ; Canny, G. O. ; Frati, L. ; Mallozzi, M. ; Frega, A. ; Caserta, D. / Non-steroidal anti-inflammatory drugs increase MRP4 expression in an endometriotic epithelial cell line in a PPARα dependent manner. In: European Review for Medical and Pharmacological Sciences. 2018 ; Vol. 22, No. 23. pp. 8487-8496.
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abstract = "OBJECTIVE: Endometriosis is a debilitating disease characterized by chronic inflammation. The transporter multidrug resistanceassociated 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 (PPARα) dependent. MATERIALS AND METHODS: MRP4 and PPARα expression was analyzed by Q-RT-PCR using TaqMan{\circledR} Master Mix and TaqMan{\circledR} 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 PPARα expression. Aspirin and diclofenac-induced increases in MRP4 expression were not observed in cells where PPARα 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 PPARα 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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T1 - Non-steroidal anti-inflammatory drugs increase MRP4 expression in an endometriotic epithelial cell line in a PPARα dependent manner

AU - Massimi, I.

AU - Pulcinelli, F. M.

AU - Piscitelli, V. P.

AU - Alemanno, L.

AU - Maltese, T.

AU - Guarino, M. L.

AU - Marci, R.

AU - Canny, G. O.

AU - Frati, L.

AU - Mallozzi, M.

AU - Frega, A.

AU - Caserta, D.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - OBJECTIVE: Endometriosis is a debilitating disease characterized by chronic inflammation. The transporter multidrug resistanceassociated 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 (PPARα) dependent. MATERIALS AND METHODS: MRP4 and PPARα 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 PPARα expression. Aspirin and diclofenac-induced increases in MRP4 expression were not observed in cells where PPARα 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 PPARα 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.

AB - OBJECTIVE: Endometriosis is a debilitating disease characterized by chronic inflammation. The transporter multidrug resistanceassociated 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 (PPARα) dependent. MATERIALS AND METHODS: MRP4 and PPARα 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 PPARα expression. Aspirin and diclofenac-induced increases in MRP4 expression were not observed in cells where PPARα 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 PPARα 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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KW - NSAID

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