Late phase endothelial cell inflammation is characterized by interferon response genes and driven by JAK/STAT, not NF kappa B

Chronic vascular inflammation underlies many diseases, including atherosclerosis, autoimmune vasculitides and transplant rejection. The resolution of inflammation is critical for proper healing and restoration of homeostasis, but the timing and signaling mechanisms involved in the return to a non-inflamed state are not well understood. Pro-adhesive gene expression, phenotype and secretome of human endothelial cells was measured in primary human aortic endothelium under chronic TNF alpha stimulation, and after short-term TNF alpha priming followed by withdrawal. The effects of NF kappa B, MAPK and JAK1/2 inhibitors on TNF alpha-induced gene expression were tested. The majority of inducible TNF alpha effectors, such as E-selectin, VCAM-1 and most chemokines, required continuous exposure for reinforcement of the altered phenotype, and were NF kappa B dependent. However, 3 h priming with TNF alpha induced late phase STAT activation and interferon response genes after 18 h, as well as enhanced ICAM-1, BST2 and CXCR3 ligand expression. Chronic activation was autonomous of continuous TNF alpha, and could be blocked by the JAK1/2 inhibitor ruxolitinib. The results demonstrate that NF kappa B is not a significant driver of the later phase of endothelial cell activation by TNF alpha, but that sustained inflammation is JAK1/2-dependent and characterized by adaptive chemokines.

Automated summary

Chronic vascular inflammation is the basis of many diseases, and resolving inflammation is crucial for restoring homeostasis. Research shows that chronic activation is JAK1/2-dependent and characterized by adaptive chemokines.