Sulindac Suppresses Nuclear Factor-κB Activation and RANTES Gene and Protein Expression in Endometrial Stromal Cells from Women with Endometriosis

126

106

Endometriosis, defined as the ectopic presence of endometrial glandular and stromal cells outside the uterine cavity, is a common benign gynecological disorder with an enigmatic pathogenesis. Many genes and gene products have been reported to be altered in endometriosis, yet some of them may not be major culprits but merely unwitting accomplices or even innocent bystanders. Therefore, the identification and apprehension of major culprits in the pathogenesis of endometriosis are crucial to the understanding of the pathogenesis and would help to develop better therapeutics for endometriosis. Although so far NF-ĸB only has left few traces of incriminating fingerprints, several lines of investigation suggest that NF-ĸB, a pivotal pro-inflammatory transcription factor, could promote and maintain endometriosis. Various inflammatory agents, growth factors, and oxidative stress activate NF-ĸB. NF-ĸB proteins themselves and proteins regulated by them have been linked to cellular transformation, proliferation, apoptosis, angiogenesis, and invasion. Interestingly, all existing and nearly all investigational medications for endometriosis appear to act through suppression of NF-ĸB activation. In endometriotic cells, NF-ĸB appears to be constitutively activated, and suppression of NF-ĸB activity by NF-ĸB inhibitors or proteasome inhibitors suppresses proliferation in vitro. Viewing NF-ĸB as a major culprit, an autoregulatory loop model can be postulated, which is consistent with existing data and, more importantly, can explain several puzzling phenomena that are otherwise difficult to interpret based on prevailing theories. This view has immediate and important implications for novel ways to treat endometriosis. Further research is warranted to precisely delineate the roles of NF-ĸB in the pathogenesis of endometriosis and to indict and convict its aiders and abettors.

Section: Existing and Investigational Therapeutics For Endometriosis:mentioning

confidence: 99%

Nuclear Factor-κB (NF-κB): An Unsuspected Major Culprit in the Pathogenesis of Endometriosis That Is Still at Large?

Guo¹

2006

126

106

“…NF-B in endometriotic stromal cell cultures activates RANTES (regulated on activation, normal T-cell-expressed and -secreted), a chemoattractant chemokine which may play an important role in the pathogenesis of endometriosis [20] . Two non-specific NF-B inhibitors, sulindac and thalidomide, have been tested in endometrial and endometriotic stromal cell cultures, showing a reduction in TNFinduced RANTES and IL-8 expression as a result of decreased NF-B activation [21,22] .…”

mentioning

confidence: 99%

Agents Blocking the Nuclear Factor-κB Pathway Are Effective Inhibitors of Endometriosis in an in vivo Experimental Model

González-Ramos

Langendonckt

Defrère

et al. 2007

Background: In vitro studies suggest that the transcription factor nuclear factor-kappa B (NF-ĸB) is implicated in the transduction of proinflammatory signals in endometriosis. The aim of this study was to investigate the involvement of NF-ĸB and the processes regulated by NF-ĸB in the initial development of endometriotic lesionsin vivo.Methods: Endometriosis was induced in nude mice by intraperitoneal injection of fluorescent-labeled menstrual endometrium. Two NF-ĸB inhibitors (BAY 11-7085 and SN-50) were injected intraperitoneally on days 0, 2 and 4 after endometriosis induction, and endometriotic lesions were recovered on day 5. Number, mass, fluorimetry and surface (morphometry) of endometriotic lesions were quantified. NF-ĸB activation, intercellular adhesion molecule (ICAM)-1 expression, cell proliferation and apoptosis were evaluated by immunohistochemical analyses and the TUNEL method. Results: Both NF-ĸB inhibitors induced a significant reduction in lesion development compared to control mice. NF-ĸB activation and ICAM-1 expression of endometriotic lesions were significantly reduced in treated mice, and cell proliferation was significantly reduced in BAY 11-7085-treated mice. Both inhibitors produced a significant increase in apoptosis of endometriotic lesions, as assessed by active caspase-3 immunostaining and the TUNEL method. Conclusion: This study demonstrates, for the first time, that the NF-ĸB pathway is implicated in the development of endometriotic lesions in vivo and that NF-ĸB inhibition reduces ICAM-1 expression and cell proliferation, but increases apoptosis of endometriotic lesions, diminishing the initial development of endometriosis in an animal model.

“…Activation of NF-ĸB is usually associated with phosphorylation of IĸB, an inhibitory protein of NF-ĸB in cytosol, by IĸB kinase (IKK), which is essential for NF-ĸB to liberate from binding with IĸB and translocate to the nucleus, where p65 binds to DNA and transcripts genes involved in a variety of process. Activation of NF-ĸB may be responsible for proliferation, angiogenesis, invasiveness and inhibition of apoptosis, and for increased production of proinflammatory cytokines and estrogens [7,8,9,10]. In women with endometriosis, NF-ĸB was found to be highly expressed in ectopic tissues compared with normal endometrium [11].…”

Section: Discussionmentioning

confidence: 99%

“…In vitro studies show that NF-ĸB can be activated in endometriotic cells by known inducers of the classic NF-ĸB pathway such as TNF-α, an important cytokines which plays a critical regulatory role in endometriosis [12]. Compounds that suppress NF-ĸB activation have been proven to modulate expressions of NF-ĸB-dependent genes which are involved in development of endometriosis [9,10]. …”

Section: Discussionmentioning

confidence: 99%

Pyrrolidine Dithiocarbamate Attenuates Nuclear Factor-ĸB Activation, Cyclooxygenase-2 Expression and Prostaglandin E<sub>2</sub> Production in Human Endometriotic Epithelial Cells

Zhang¹,

Chang

et al. 2011

Background: The nuclear factor-ĸB (NF-ĸB) pathway activates many of the target genes that are critical to the initiation and establishment of endometriosis. We sought to examine the potential application of pyrrolidine dithiocarbamate (PDTC), a potent NF-ĸB inhibitor, in the treatment of endometriosis. Methods: The phosphorylation of IĸB, expression of nuclear p65 protein and NF-ĸB DNA binding in endometriotic epithelial cells (EECs), endometriotic eutopic epithelial cells (EuECs) and normal epithelial cells (NECs) were detected by Western blot analysis and electrophoretic mobility shift assay. Cyclooxgenase-2 (COX-2) gene and protein expressions in EECs were measured by RT-PCR and Western blot analysis. Prostaglandin E₂ (PGE₂) production of EECs was measured by ELISA. Results: PDTC in the absence or presence of tumor necrosing factor-α (TNF-α) showed stronger inhibitory effects on IĸB phosphorylation, expression of nuclear p65 protein and NF-ĸB DNA-binding activity in EECs than in EuECs or NECs. Pretreatment of EECs with PDTC resulted in a dose-dependent reduction in the TNF-α-induced expressions of COX-2 at gene and protein levels, as well as a reduction of PGE₂ synthesis. Conclusion: PDTC may represent a novel therapeutic strategy for treatment of endometriosis.