RETINOIC ACID-STIMULATED INTERCELLULAR-ADHESION MOLECULE-1 EXPRESSIONON SK-N-SH CELLS - CALCIUM CALMODULIN-DEPENDENT PATHWAY/

Intercellular adhesion molecule-1 (ICAM-1) is an important cell surfac e adhesion receptor of the immune system. Its cell surface expression on a wide variety of cells, including cancer cells, is regulated by va rious proinflammatory cytokines. In the present study, we investigated the role of calcium (Ca2+) and calmodulin (CaM) in the retinoic acid and gamma-interferon (IFN-gamma) signaling in the human neuroblastoma cell line SK-N-SH for up-regulating ICAM-1 expression. A 24-h incubati on in the presence of Ca2+-mobilizing agents (A23187 and thapsigargin) resulted in the induction of ICAM-1 expression. Both Ca2+-mobilizing agents stimulated ICAM-1 expression additively to IFN-gamma but not to retinoic acid, suggesting that IFN-gamma does not use Ca2+ to stimula te ICAM-1, whereas retinoic acid might use it in part. As a second mes senger, Ca2+ can be coupled with calmodulin. Using calmodulin inhibito rs (W7 and calmidazolium), we found that retinoic acid-stimulated, A23 187-stimulated, and thapsigargin-stimulated but not IFN-gamma-stimulat ed ICAM-1 were inhibited. Calmodulin signaling elicited by retinoic ac id was an early event occurring within the first h of retinoic acid tr eatment, providing evidence that they may both be coupled to regulate gene expression. Using a novel CaM kinase II inhibitor, KN-62, we demo nstrated that retinoic acid stimulated ICAM-1 expression in a CaM kina se II-dependent fashion. The mechanisms whereby CaM kinase II mediates retinoic acid activity on ICAM-1 expression remain to be elucidated.