TNFα-induced IKKβ complex activation influences epithelial, but not stromal cell survival in endometriosis.

Kocbek, Vida; Grandi, Giovanni; Blank, Fabian; Wotzkow Alvarez, Carlos; Bersinger, Nick A.; Mueller, Michael D.; Kyo, Satoru; Mc Kinnon, Brett D. (2016). TNFα-induced IKKβ complex activation influences epithelial, but not stromal cell survival in endometriosis. Molecular human reproduction MHR, 22(11), pp. 768-777. Oxford University Press 10.1093/molehr/gaw054

[img]
Preview
Text
Final article.pdf - Accepted Version
Available under License Publisher holds Copyright.

Download (4MB) | Preview
[img] Text
gaw054.pdf - Published Version
Restricted to registered users only until 1 December 2019.
Available under License Publisher holds Copyright.

Download (794kB) | Request a copy

STUDY QUESTION Can the activity of the IκB kinase (IKKβ) complex in endometriotic cells contribute to endometriotic lesion survival? SUMMARY ANSWER There is a constitutive activity of the IKKβ catalytic complex in peritoneal and deeply infiltrating lesions that can influence epithelial, but not stromal cell viability. WHAT IS KNOWN ALREADY Endometriotic lesions exist in an inflammatory microenvironment with higher local concentrations of cytokines, such as tumour necrosis factor α (TNFα). TNFα stimulates the activation of the IKKβ complex, an important nodal point in multiple signalling pathways that influence gene transcription, proliferation and apoptosis. However, few data on the regulation of IKKβ in endometriotic tissue are currently available. STUDY DESIGN, SIZE, DURATION A retrospective analysis of endometriotic tissue from peritoneal, ovarian and deeply infiltrating lesions from 37 women. PARTICIPANTS/MATERIALS, SETTING, METHODS Basal and activated (phosphorylated) IKKβ concentrations were analysed by western blotting and immunohistochemistry. The relationship between the expression and activation of these proteins and peritoneal fluid (TNFα) concentrations, measured via ELISA, was examined. A subsequent in vitro analysis of TNFα treatment on the activation of IKKβ and the effect on epithelial and stromal cell viability by its inhibition with PS1145 was also performed. MAIN RESULTS AND ROLE OF CHANCE Levels of the phosphorylated IKKβ complex in endometriotic lesions had a significant positive correlation with peritoneal fluid TNFα concentrations. Phosphorylated IKKβ complex was more prevalent in peritoneal and deeply infiltrating endometriosis lesions compared with ovarian lesions. IKKβ was present in both epithelial and stromal cells in all lesions but active IKKβ was limited to epithelial cells. TNFα stimulated an increased expression of phosphorylated IKKβ and the inhibition of this kinase with PS1145 significantly influenced ectopic epithelial cells viability but not eutopic epithelial cells, or endometrial stromal cells. LIMITATIONS, REASONS FOR CAUTION In vitro analysis on epithelial cells was performed with immortalized cell lines and not primary cell cultures and only low sample numbers were available for the study. WIDER IMPLICATIONS OF THE FINDINGS The regulation of aberrant signalling pathways represents a promising yet relatively unexplored area of endometriosis progression. The IKKβ complex is activated by inflammation and is critical nodal point of numerous downstream kinase-signalling pathways, including NFκB (nuclear factor κB), mTOR (mammalian target of rapamycin) and BAD (Bcl2-antagonist of cell death). This study shows a significant relationship between peritoneal fluid TNFα and IKKβ activation in epithelial cells that will have significant consequences for the continued survival of these cells at ectopic locations through the regulation of downstream pathways. LARGE SCALE DATA None. STUDY FUNDING/COMPETING INTERESTS The study was funded by the Swiss National Science Foundation (Grant Number 320030_140774). The authors have no conflict of interest to declare.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Pneumology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)
04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Gynaecology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Forschungsbereich Mu50 > Forschungsgruppe Pneumologie (Erwachsene)
09 Interdisciplinary Units > Microscopy Imaging Center MIC
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DCR Services > Core Facility Live Cell Imaging (LCI)

UniBE Contributor:

Kocbek, Vida; Blank, Fabian; Wotzkow Alvarez, Carlos; Bersinger, Nick A.; Mueller, Michael and Mc Kinnon, Brett

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1360-9947

Publisher:

Oxford University Press

Language:

English

Submitter:

Rahel Holderegger

Date Deposited:

26 Jan 2017 16:13

Last Modified:

19 Feb 2019 14:53

Publisher DOI:

10.1093/molehr/gaw054

PubMed ID:

27542948

Uncontrolled Keywords:

DIE; IKK; TNF; endometrioma; endometriosis; inflammation; kinase; peritoneal; signalling; transcription factor

BORIS DOI:

10.7892/boris.93350

URI:

https://boris.unibe.ch/id/eprint/93350

Actions (login required)

Edit item Edit item
Provide Feedback