Zünd G, Uezono S, Stahl G L, Dzus A L, McGowan F X, Hickey P R, Colgan S P
Department of Anesthesia, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Am J Physiol. 1997 Nov;273(5):C1571-80. doi: 10.1152/ajpcell.1997.273.5.C1571.
Intercellular adhesion molecule 1 (ICAM-1) is an important molecule in promotion of polymorphonuclear neutrophil transendothelial migration during inflammation. Coincident with many inflammatory diseases is tissue hypoxia. Thus we hypothesized that combinations of hypoxia and inflammatory stimuli may differentially regulate expression of endothelial ICAM-1. Human endothelial cells were exposed to hypoxia in the presence or absence of added lipopolysaccharide (LPS) and examined for expression of functional ICAM-1. Although hypoxia alone did not induce ICAM-1, the combination of LPS and hypoxia enhanced (3 +/- 0.4-fold over normoxia) ICAM-1 expression. Combinations of hypoxia and LPS significantly increased lymphocyte binding, and such increases were inhibited by addition of anti-ICAM-1 antibodies or antisense oligonucleotides. Hypoxic endothelia showed a > 10-fold increase in sensitivity to inhibitors of proteasome activation, and combinations of hypoxia and LPS enhanced proteasome-dependent cytoplasmic-to-nuclear localization of the nuclear transcription factor-kappa B p65 (Rel A) subunit. Such proteasome activation correlated with hypoxia-evoked decreases in both extracellular and intracellular pH. We conclude from these studies that endothelial hypoxia provides a novel, proteasome-dependent stimulus for ICAM-1 induction.
细胞间黏附分子1（ICAM-1）是炎症过程中促进多形核中性粒细胞跨内皮迁移的重要分子。许多炎症性疾病都伴有组织缺氧。因此，我们推测缺氧与炎症刺激的组合可能会差异性地调节内皮细胞ICAM-1的表达。将人内皮细胞置于有或无脂多糖（LPS）添加的缺氧环境中，并检测功能性ICAM-1的表达。虽然单独缺氧不会诱导ICAM-1，但LPS与缺氧的组合可增强ICAM-1的表达（比常氧高出3±0.4倍）。缺氧与LPS的组合显著增加淋巴细胞结合，且添加抗ICAM-1抗体或反义寡核苷酸可抑制这种增加。缺氧内皮细胞对蛋白酶体激活抑制剂的敏感性增加了10倍以上，缺氧与LPS的组合增强了核转录因子-κB p65（Rel A）亚基蛋白酶体依赖性的胞质到核定位。这种蛋白酶体激活与缺氧引起的细胞外和细胞内pH值降低相关。我们从这些研究中得出结论，内皮细胞缺氧为ICAM-1的诱导提供了一种新的、蛋白酶体依赖性的刺激。
