Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, United States of America.
Vascul Pharmacol. 2022 Oct;146:107090. doi: 10.1016/j.vph.2022.107090. Epub 2022 Jul 29.
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 TNFα stimulation, and after short-term TNFα priming followed by withdrawal. The effects of NFκB, MAPK and JAK1/2 inhibitors on TNFα-induced gene expression were tested. The majority of inducible TNFα effectors, such as E-selectin, VCAM-1 and most chemokines, required continuous exposure for reinforcement of the altered phenotype, and were NFκB dependent. However, 3 h priming with TNFα 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 TNFα, and could be blocked by the JAK1/2 inhibitor ruxolitinib. The results demonstrate that NFκB is not a significant driver of the later phase of endothelial cell activation by TNFα, but that sustained inflammation is JAK1/2-dependent and characterized by adaptive chemokines.
慢性血管炎症是许多疾病的基础，包括动脉粥样硬化、自身免疫性血管炎和移植排斥反应。炎症的消退对于适当的愈合和内稳态的恢复至关重要，但是对于恢复非炎症状态的时间和信号机制还不是很清楚。本研究在慢性 TNFα 刺激下，以及在短期 TNFα 引发后撤回的情况下，测量了原发性人主动脉内皮细胞中促黏附基因表达、人内皮细胞表型和分泌组。测试了 NFκB、MAPK 和 JAK1/2 抑制剂对 TNFα 诱导的基因表达的影响。大多数诱导型 TNFα 效应物，如 E-选择素、VCAM-1 和大多数趋化因子，需要持续暴露才能增强改变的表型，并且依赖于 NFκB。然而，TNFα 刺激 3 小时可诱导晚期 STAT 激活和干扰素反应基因 18 小时后，以及增强的 ICAM-1、BST2 和 CXCR3 配体表达。慢性激活不依赖于持续的 TNFα，并且可以被 JAK1/2 抑制剂鲁索利替尼阻断。结果表明，NFκB 不是 TNFα 诱导内皮细胞活化后期的主要驱动因素，但是持续的炎症是 JAK1/2 依赖性的，其特征是适应性趋化因子。
