Constitutive and Tumor Necrosis Factor-Alpha-Stimulated Activation of Nuclear Factor-KappaB in Immortalized Endometriotic Cells and Their Suppression by Trichostatin A

Abstract

Objective(s): To determine whether nuclear factor-ĸB (NF-ĸB) is constitutively and tumor necrosis factor (TNF)-dependently activated in endometriotic cells, whether trichostatin A (TSA) can suppress NF-ĸB activation and suppress TRAF2/6 and TAK1, and whether TSA and caffeic acid phenyl ester can suppress constitutive and H₂O₂-stimulated proliferation of endometriotic cells. Methods: Two endometriotic cell lines and an endometrial stromal cell line were used as an in vitro model. Electrophoretic mobility shift analysis was used to determine NF-ĸB activation and possible suppression by TSA. Western blot analysis was used to determine whether TSA suppresses phosphorylation of IĸBα, phosphorylation of p65 in the cytoplasm and nuclear translocation, and the expression of TRAF2/6 and TAK1. Results: NF-ĸB was constitutively activated in endometriotic cells, but only minimally in endometrial cells. TNFα stimulation activated NF-ĸB through induction of IĸB phosphorylation, but the activation can be suppressed by TSA. TSA also attenuated constitutive and TNF-dependent p65 phosphorylation and nuclear translocation in endometriotic cells. TRAF2, TRAF6 and TAK1 were constitutively activated and were unaffected by TSA treatment. Conclusions: NF-ĸB activation may play a critical role in the pathogenesis in endometriosis. Targeting NF-ĸB with histone deacetylase inhibitors or other compounds might hold promise as novel therapeutics for endometriosis.

Developmental exposure of fetal ovaries and fetal germ cells to endometriosis in an endometriosis model causes differential gene expression in the preimplantation embryos of the first-generation and second-generation embryos

“…Down-regulation of Nfkbia was not found in F2 embryos, which may again indicate germ cell exposure to endometriosis may only reprogram expression of select genes. Others have also found NF-κB regulation anomalies associated with endometriosis (51). …”

Effect of Caffeic Acid Phenethyl Ester on Intra-Abdominal Adhesion in Rats

“…Administration of CAPE has been shown to completely block the production of ROS from activated neutrophils. Beyond that, CAPE can inhibit neutrophil infiltration during inflammatory process and protect tissues from oxidative stress due to reactive oxygen species and reduce the lipid peroxidation [6,7,8,9,10]. In other words, this effect is exerted by regulation of inflammation, immunomodulation and oxidation.…”

“…It has been widely used as an antioxidant against various oxidative processes in animal models [7,8,9,10,11,12,13,14]. …”

Pharmacologic therapies in endometriosis: a systematic review

“…Cultures of epithelial and hESCs to which this substance is added display attenuation of proliferative capacity and invasiveness. The expression of E-cadherin, a key intercellular protein in the formation of adherence junctions, is enhanced, and NF-kB activation is suppressed (200,201). Similarly, human adenomyotic cells viability is inhibited by trichostatin A in a concentration-dependent fashion through mechanisms of both cytotoxicity and cell cycle arrest (202).…”