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Peroxisome proliferator-activated receptor-gamma ligand reduced tumor necrosis factor-alpha-induced interleukin-8 production and growth in endometriotic stromal cells.

Ohama Y, Harada T, Iwabe T, Taniguchi F, Takenaka Y, Terakawa N

Department of Obstetrics and Gynecology, Tottori University School of Medicine, Yonago, Japan. hinakuu@grape.med.tottori-u.ac.jp

OBJECTIVE: To evaluate the influence of peroxisome proliferator-activated receptor-gamma (PPAR gamma) ligand (pioglitazone) on tumor necrosis factor-alpha (TNF-alpha)-induced interleukin-8 (IL-8) expression in endometriotic stromal cells (ESCs) and on proliferation of ESCs. DESIGN: Prospective study. SETTING: Department of Obstetrics and Gynecology, Tottori University Hospital, Yonago, Japan. PATIENT(S): Twenty-seven patients who underwent laparoscopic surgery. INTERVENTION(S): The ESCs were obtained from the chocolate cyst linings of ovaries. MAIN OUTCOME MEASURE(S): The expression of PPAR gamma gene and protein was determined by reverse transcriptase-polymerase chain reaction (RT-PCR) and immunocytochemistry. We determined the effect of pioglitazone on the production of TNF-alpha-induced IL-8 protein in culture supernatant of ESCs using ELISA. The effect of pioglitazone on TNF-alpha-induced proliferation of ESCs was evaluated by 5-bromo-2'-deoxyuridine proliferation assay. The activation of nuclear factor (NF)-kappaB in ESCs was evaluated by Western blot analyses and NF-kappaB transcription factor assays. RESULT(S): Immunocytochemistry and RT-PCR revealed the expression of PPAR gamma gene and protein in ESCs. The PPAR gamma protein was predominantly located in the cell nucleus. Measurement of IL-8 protein by ELISA showed that adding TNF-alpha (100 pg/mL) significantly increased IL-8 protein. Treating ESCs with 0.1-10 microM of pioglitazone significantly reduced the TNF-alpha-induced IL-8 production. The presence of 0.1-10 microM of pioglitazone significantly suppressed growth of ESCs. The TNF-alpha increased the expression of phosphorylation of inhibitor kappaB (I kappaB). Adding pioglitazone (10 microM) did not influence the expression of phosphorylated inhibitor kappaB (I kappaB). The TNF-alpha markedly increased the intranuclear concentration of p65, and adding pioglitazone (10 microM) significantly reduced the concentration of p65. CONCLUSION(S): The present study demonstrates for the first time that PPAR gamma is expressed in ESCs, and that pioglitazone reduced IL-8 secretion and the proliferation of ESCs. The PPAR gamma ligand may be an attractive therapeutic agent for endometriosis.

Published 15 February 2008 in Fertil Steril, 89(2): 311-7.
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