Second messenger regulation of cell adhesion molecule expression by astrocytes.

摘要

Intercellular adhesion molecule-1 (ICAM-1) and vascular cell ashesion molecule-1 (VCAM-1) are important mediators of immune and inflammatory processes in diseases of the central nervous system (CNS) such as multiple sclerosis (MS), experimental allergic encephalomyelitis (EAE), and AIDS dementia complex (ADC). Two cytokines, tumor necrosis factor-alpha (TNF-{dollar}alpha{dollar}) and interleukin-1 beta (IL-1{dollar}beta{dollar}), are strong inducers of ICAM-1 and VCAM-1 gene expression by astrocytes. The expression of these cell adhesion molecules is positively correlated with the aforementioned inflammatory diseases, as are IL-1{dollar}beta{dollar} and TNF-{dollar}alpha{dollar}. The intracellular signaling pathways utilized by the two cytokines to induce adhesion molecule expression were investigated.; Using a pharmacological approach it was demonstrated that both IL-1{dollar}beta{dollar} and TNF-{dollar}alpha{dollar} use protein kinase C (PKC) as a second messenger to induce ICAM-1 gene expression by astrocytes. Prolonged phorbol ester treatment, resulted in diminished PKC protein expression by astrocytes, and a concomitant diminution of cytokine-induced ICAM-1 gene expression. Phosphatidylcholine-phospholipase C activity was also required for IL-1{dollar}beta{dollar} and TNF-{dollar}alpha{dollar} induction of the ICAM-1 gene. Increasing cAMP levels within the astrocyte and presumably activating cAMP dependent protein kinase (PKA), had no effect on ICAM-1 or VCAM-1 gene expression by astrocytes, demonstrating that PKA mediated signaling pathways are not required to induce adhesion molecule gene expression. However, elevation of cAMP levels within astrocytes suppressed IL-1{dollar}beta{dollar} and TNF-{dollar}alpha{dollar} induction of ICAM-1 and VCAM-1 gene expression by astrocytes. This effect was potentiated by the type IV specific phosphodiesterase inhibitor rolipram. Delineating the signaling pathways utilized by IL-1{dollar}beta{dollar} and TNF-{dollar}alpha{dollar} to induce cell adhesion molecule expression and understanding mechanisms to downmodulate this pathway will aid in regulating immune responses in the CNS.