Iron overload modulated nuclear factor kappa B activation in human endometrial stromal cells as a mechanism postulated in endometriosis pathogenesis

Capsule:
Iron overload activates the nuclear factor kappa-B pathway, increasing the expression of intercellular adhesion molecule-1 (ICAM-1) and the secretion of soluble ICAM-1 by endometrial stromal cells, suggesting a new mechanism that may be involved in the pathogenesis of endometriosis.

Authors:
Carlos Patricio Alvarado-Díaz, Ph.D., Marco Tulio Núñez, Ph.D., Luigi Devoto, M.D., Reinaldo González-Ramos, M.D., Ph.D.

Volume 103, Issue 2, Pages 439-447

Abstract:

Objective:
To evaluate the effect of iron overload on nuclear factor kappa-B (NF-κB) activation in human endometrial stromal cells (ESCs).

Design:
Experimental study.

Setting:
University hospital research laboratory.

Patient(s):
Ten healthy women.

Intervention(s):
Isolated ESCs from endometrial biopsies were incubated with 50 μM FeSO4 or vehicle. The NF-κB inhibitor [5-(p-fluorophenyl)-2-ureido] thiophene-3-carboxamide (TPCA-1), which inhibits IKKβ, the kinase of IκBα (inhibitory protein of NF-κB), was used to prevent iron overload–stimulated NF-κB changes in ESCs.

Main Outcome Measure(s):
NF-κB activation was assessed by p65:DNA-binding activity immunodetection assay. IκBα, p65, and intercellular adhesion molecule (ICAM)-1 proteins expression was evaluated by Western blots. ESC soluble ICAM (sICAM)-1 secretion was measured by ELISA using conditioned medium.

Result(s):
Iron overload increased p65:DNA-binding activity and decreased IκBα and p65 cytoplasmic expression in ESCs after 30 minutes of incubation as compared with the basal condition. ESC ICAM-1 expression and sICAM-1 secretion were higher after 24 hours of iron overload treatment than in the absence of treatment. TPCA-1 prevented the iron overload–induced increase of p65:DNA binding and IκBα degradation.

Conclusion(s):
Iron overload activates IKKβ in ESCs, stimulating the NF-κB pathway and increasing ICAM-1 expression and sICAM-1 secretion. These results suggest that iron overload induces a proendometriotic phenotype on healthy ESCs, which could participate in endometriosis pathogenesis and development.

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