Tumor necrosis factor α up-regulates endometrial milk fat globule-epidermal growth factor 8 protein production via nuclear factor κB activation, resulting in cell migration of epithelial cells

Fertil Steril. 2014 Feb;101(2):552-9. doi: 10.1016/j.fertnstert.2013.10.032. Epub 2013 Nov 18.


Objective: To explore the role of tumor necrosis factor (TNF) α, an early embryonic product, on endometrial epithelial cell migration and endometrial milk fat globule-epidermal growth factor 8 protein (MFG-E8) production.

Design: In vitro study.

Setting: Academic center.

Intervention(s): Ishikawa cells, used as surrogates for human epithelial cells, were treated with and without TNF-α.

Main outcome measure(s): Effect of TNF-α on intracellular MFG-E8 protein was evaluated with the use of ELISA, Western blot, and subcellular fractionation. Specific inhibitors were used to study TNF-α mechanism of action. Effect of TNF-α on cell migration was studied with the use of a wound healing assay and reorganization of E-cadherin.

Result(s): TNF-α induced: 1) significant up-regulation of MFG-E8 intracellular protein, which was attenuated by pretreatment with a specific inhibitor of nuclear factor κB; 2) increased transcription of MFG-E8 and other proinflammatory factors, such as interleukins 6 and 8, which were suppressed by cotreatment with hCG; and 3) significant cell migration with E-cadherin remodeling, changes associated with subcellular MFG-E8 relocalization.

Conclusion(s): TNF-α up-regulates endometrial epithelial cell migration and MFG-E8 production, which are critical steps required for the endometrial changes during menstrual cycle as well as during embryonic attachment and invasion.

Keywords: Human endometrium; MFG-E8; TNF-α; cell migration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Surface / biosynthesis*
  • Cell Line, Tumor
  • Cell Movement / physiology*
  • Endometrium / metabolism*
  • Epithelial Cells / metabolism*
  • Female
  • Humans
  • Milk Proteins / biosynthesis*
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism*
  • Tumor Necrosis Factor-alpha / physiology*
  • Up-Regulation / physiology*


  • Antigens, Surface
  • MFGE8 protein, human
  • Milk Proteins
  • NF-kappa B
  • Tumor Necrosis Factor-alpha