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

NF-κB-inducing kinase (NIK) 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 it 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 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 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, was required for the inflammatory response. Endothelial inflammatory activation induced by synovial fluid from rheumatoid arthritis patients was significantly reduced by NIK knock-down, suggesting that NIK-mediated alternative activation of canonical NF-κB signaling is a key driver of pathological inflammatory activation of ECs. Targeting NIK may provide a novel approach to treating chronic inflammatory diseases.