NIK-IKK complex interaction controls NF-κB-dependent inflammatory activation of endothelium in response to LTβR ligation

J Cell Sci. 2019 Apr 3;132(7):jcs225615. doi: 10.1242/jcs.225615.

Abstract

NF-κB-inducing kinase (NIK; also known as MAP3K14) is a central regulator of non-canonical NF-κB signaling in response to stimulation of TNF receptor superfamily members, such as the lymphotoxin-β receptor (LTβR), and is implicated in pathological angiogenesis associated with chronic inflammation and cancer. Here, we identify a previously unrecognized role of the LTβR-NIK axis during inflammatory activation of human endothelial cells (ECs). Engagement of LTβR-triggered canonical and non-canonical NF-κB signaling promoted expression of inflammatory mediators and adhesion molecules, and increased immune cell adhesion to ECs. Sustained LTβR-induced inflammatory activation of ECs was NIK dependent, but independent of p100, indicating that the non-canonical arm of NF-κB is not involved. Instead, prolonged activation of canonical NF-κB signaling, through the interaction of NIK with IκB kinase α and β (also known as CHUK and IKBKB, respectively), was required for the inflammatory response. Endothelial inflammatory activation induced by synovial fluid from rheumatoid arthritis patients was significantly reduced by NIK knockdown, suggesting that NIK-mediated alternative activation of canonical NF-κB signaling is a key driver of pathological inflammatory activation of ECs. Targeting NIK could thus provide a novel approach for treating chronic inflammatory diseases.

Keywords: Endothelial cells; Inflammation; LTβR; Lymphotoxin-β receptor; NF-κB-inducing kinase; NIK.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Basic Helix-Loop-Helix Transcription Factors
  • Cell Line
  • Cells, Cultured
  • Endothelial Cells / metabolism*
  • Endothelium / metabolism
  • Gene Expression Regulation
  • Humans
  • Lymphotoxin beta Receptor / metabolism*
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Neovascularization, Pathologic / metabolism
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Signal Transduction*

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Lymphotoxin beta Receptor
  • NF-kappa B
  • endothelial PAS domain-containing protein 1
  • Protein-Serine-Threonine Kinases
  • NF-kappa B kinase