INTERLEUKIN-1-BETA-MEDIATED AND TUMOR NECROSIS FACTOR-ALPHA-MEDIATED REGULATION OF ICAM-1 GENE-EXPRESSION IN ASTROCYTES REQUIRES PROTEIN-KINASE-C ACTIVITY

Several adhesion molecules including intercellular adhesion molecule-1 (ICAM-1) are expressed by astrocytes, the predominant glial cell of t he central nervous system (CNS). Such molecules are important in the t rafficking of leukocytes to sites of inflammation, and in lymphocyte a ctivation. ICAM-1 is constitutively expressed by neonatal rat astocyte s, and expression is enhanced by the proinflammatory cytokines interle ukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma), with IL-1 beta and TNF-alpha being the s trongest inducers. In this study, we have examined the nature of the s econd messengers involved in ICAM-1 gene expression induced by the cyt okines IL-1 beta and TNF-alpha. Our results indicate that stimuli rela ted to protein kinase C (PKC) such as the phorbol ester phorbol 12-myr istate 13-acetate (PMA) and calcium ionophore A23187 increase ICAM-1 m RNA expression, whereas cyclic nucleotide analogs and PKA agonists hav e no effect. Pharmacologic inhibitors of PKC such as H7, H8, and calph ostin C inhibit ICAM-1 gene expression inducible by IL-1 beta and TNF- alpha. Prolonged treatment of astrocytes with PMA results in a time-de pendent downregulation of the PKC isoforms alpha, delta, and epsilon, and a concomitant diminution of ICAM-1 mRNA expression induced by IL-1 beta, TNF-alpha, and PMA itself at specific time points post-PMA trea tment. These data, collectively, demonstrate a role for various PKC is oforms in IL-1 beta and TNF-alpha enhancement of ICAM-1 gene expressio n in rat astrocytes. (C) 1995 Wiley-Liss, Inc.