TRIM14 promotes endothelial activation via activating NF-κB signaling pathway.

Endothelial activation by proinflammatory cytokines is closely associated to the pathogenesis of atherosclerosis and other vascular diseases; however, the molecular mechanisms controlling endothelial activation are not fully understood. Here we identify TRIM14 as a new positive regulator of endothelial activation via activating NF-κB signal pathway. TRIM14 is highly expressed in human vascular endothelial cells (ECs) and markedly induced by inflammatory stimuli such as TNF-α, IL-1β, and LPS. Overexpression of TRIM14 significantly increased the expression of adhesion molecules such as VCAM-1, ICAM-1, E-selectin, and cytokines such as CCL2, IL-8, CXCL-1, and TNF-α in activated ECs and by which it facilitated monocyte adhesion to ECs. Conversely, knockdown of TRIM14 has opposite effect on endothelial activation. Upon TNF-α stimulation, TRIM14 is recruited to IKK complex via directly binding to NEMO and promotes the phosphorylation of IκBα and p65, which is dependent on its K63-linked ubiquitination. Meanwhile, p65 can directly bind to the promoter regions of human TRIM14 gene and control its mRNA transcription. Finally, TRIM14 protein level is significantly upregulated in mouse and human atheroma compared to normal arteries. Taken together, these results indicate that TRIM14-NF-κB forms a positive feedback loop to enhance EC activation and TRIM14 may be a potential therapeutic target for vascular inflammatory diseases such as atherosclerosis.