HYPOXIA ENHANCES INDUCTION OF ENDOTHELIAL ICAM-1 - ROLE FOR METABOLIC-ACIDOSIS AND PROTEASOMES

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 tis sue hypoxia. Thus we hypothesized that combinations of hypoxia and inf lammatory stimuli may differentially regulate expression of endothelia l ICAM-1. Human endothelial cells were exposed to hypoxia in the prese nce or absence of added lipopolysaccharide (LPS) and examined for expr ession of functional ICAM-1. Although hypoxia alone did not induce ICA M-1, the combination of LPS and hypoxia enhanced (3 +/- 0.4-fold over normoxia) ICAM-1 expression. Combinations of hypoxia and LPS significa ntly increased lymphocyte binding, and such increases were inhibited b y addition of anti-ICAM-1 antibodies or antisense oligonucleotides. Hy poxic endothelia showed a >10-fold increase in sensitivity to inhibito rs of proteasome activation, and combinations of hypoxia and LPS enhan ced proteasome-dependent cytoplasmic-to-nuclear localization of the nu clear transcription factor-kappa B p65 (Rel A) subunit. Such proteasom e activation correlated with hypoxia-evoked decreases in both extracel lular and intracellular pH. We conclude from these studies that endoth elial hypoxia provides a novel, proteasome-dependent stimulus for ICAM -1 induction.