Intercellular adhesion molecule-1 (ICAM-1) is an important cell surface adhesion receptor of the immune system. Its cell surface expression on a wide variety of cells, including cancer cells, is regulated by various proinflammatory cytokines. In the present study, we investigated the role of calcium (Ca2+) and calmodulin (CaM) in the retinoic acid and γ-interferon (IFN-γ) signaling in the human neuroblastoma cell line SK-N-SH for up-regulating ICAM-1 expression. A 24-h incubation 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-γ but not to retinoic acid, suggesting that IFN-γ does not use Ca2+ to stimulate ICAM-1, whereas retinoic acid might use it in part. As a second messenger, Ca2+ can be coupled with calmodulin. Using calmodulin inhibitors (W7 and calmidazolium), we found that retinoic acid-stimulated, A23187-stimulated, and thapsigargin-stimulated but not IFN-γ-stimulated ICAM-1 were inhibited. Calmodulin signaling elicited by retinoic acid was an early event occurring within the first h of retinoic acid treatment, providing evidence that they may both be coupled to regulate gene expression. Using a novel CaM kinase II inhibitor, KN-62, we demonstrated that retinoic acid stimulated ICAM-1 expression in a CaM kinase II-dependent fashion. The mechanisms whereby CaM kinase II mediates retinoic acid activity on ICAM-1 expression remain to be elucidated.


This work was supported by a grant from the Arthritis Society of Canada and from the Natural Science and Engineering Research Council of Canada. M. B. is the recipient of a studentship from the Arthritis Society of Canada. M. A. is the recipient of a scholarship from the Fonds de la Recherche en Santé du Québec.

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