EXPRESSION AND REGULATION OF ADHESION MOLECULES IN CARDIAC-CELLS BY CYTOKINES - RESPONSE TO ACUTE-HYPOXIA

Adhesion molecules mediate inflammatory myocardial injury after ischem ia/reperfusion. Cytokine release and hypoxia are features of acute isc hemia that may influence expression of these molecules. Accordingly, w e studied intercellular adhesion molecule (ICAM) and vascular cell adh esion molecule (VCAM) responses to cytokines and acute hypoxia in cult ured myocardial cells. Northern blot analysis and immunoassay showed t hat the proinflammatory cytokines interleukin-1 beta (IL-1 beta) and t umor necrosis factor-alpha stimulated concentration-dependent increase s in ICAM and VCAM mRNA and protein. In both cardiac myocytes and fibr oblasts, pretreatment with a specific inhibitor of nuclear transcripti on factor-kappa B (NF-kappa B) prevented cytokine induction of both mo lecules. We also found that inhibition of tyrosine kinase and p38/RK ( stress-activated protein kinase) pathways prevented IL-1 beta-induced ICAM and VCAM protein synthesis, whereas extracellular signal-regulate d protein kinase (ERK1/ERK2) inhibition did not. Neither hypoxia (0% O -2 for 6 hours) alone nor hypoxia/reoxygenation had any significant ef fect on ICAM and VCAM nRNA. However, hypoxia did enhance IL-1 beta-ind uced ICAM mRNA expression in myocytes. As a possible mechanism of this synergistic action on CAM expression, hypoxia induced. a time-depende nt increase in the DNA binding activity of both NF-kappa B and activat or protein-1 (AP-1), two transcription factors important for cell adhe sion molecule expression. In contrast to the enhanced ICAM mRNA induce d by IL-1 beta during hypoxia, however, protein levels for this adhesi on molecule were unchanged beyond IL-1 beta-stimulated levels, suggest ing posttranscriptional and/or posttranslational control mechanisms. W e conclude that cytokines regulate ICAM and VCAM mRNA and protein in b oth cardiac myocytes and fibroblasts. Furthermore, adhesion molecule i nduction requires translocation of at least two transcription factors, NF-kappa B and AP-1.