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Tumor Necrosis Factor (TNF) Receptor Expression Determines Keratinocyte Fate upon Stimulation with TNF-Like Weak

Xuening Wang1, Dan Cheng2, Guanglei Hu1

  • 1Department of Dermatology, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China.

Mediators of Inflammation
|December 31, 2019
PubMed

Insights

Tumor necrosis factor- (TNF-) like weak inducer of apoptosis (TWEAK) and fibroblast growth factor-inducible 14 (Fn14) signaling regulates keratinocyte fate. The Fn14-TRAF2-TNFR axis mediates TWEAK

Area of Science:

  • Cell Biology
  • Immunology
  • Dermatology

Background:

  • Tumor necrosis factor- (TNF-) like weak inducer of apoptosis (TWEAK) and fibroblast growth factor-inducible 14 (Fn14) interaction influences keratinocyte fate.
  • The precise mechanism of TWEAK-mediated keratinocyte regulation via TNF receptors (TNFR) 1 and 2 is not fully understood.

Purpose of the Study:

  • To comprehensively investigate the roles of Fn14, TNFR1/2, and associated molecules in keratinocyte fate.
  • To elucidate the structural basis of TWEAK-Fn14 interactions in regulating cellular outcomes.

Main Methods:

  • Stimulation of normal and TNFR2-overexpressing keratinocytes with TWEAK.
  • Immunoprecipitation and Western blotting to analyze molecular associations.
  • Investigation of TNFR-associated factor 2 (TRAF2) binding.

Main Results:

  • TWEAK induces apoptosis in normal keratinocytes (TNFR1-dominant) and proliferation in TNFR2-overexpressing keratinocytes, independent of TNF-α.
  • TRAF2 binding to Fn14, cIAP1, and TNFR1/2 was confirmed; TRAF2 inhibition reversed TWEAK's effects.
  • TWEAK-Fn14 interaction increased TNFR1-associated death domain protein and caspase-8 in normal keratinocytes and promoted cIAP1 import in TNFR2-overexpressing cells.

Conclusions:

  • The Fn14-TRAF2-TNFR signaling axis mediates TWEAK's regulation of keratinocyte fate.
  • This regulation may involve TNF-α-independent TNFR signal transduction.

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