Immunoregulatory effects of interferon-β and interacting cytokines on human vascular endothelial cells implications for multiple sclerosis and other autoimmune diseases

Abstract

The mechanism(s) of action responsible for the anti-inflammatory effects mediated by interferon (IFN)-β are still elusive although suggestions include anti-viral effects, the enhancement of natural killer (NK) or suppressor T cell activity and opposition to the effects of inflammatory cytokines. As vascular endothelial cells are active participants in inflammatory and demyelinating processes, we decided to examine the effects of IFN-β on the expression of major histocompatibility complex (MHC) gene products and intercellular adhesion molecule (ICAM)-1 on human vascular endothelial cells (ECs). Human umbilical ECs demonstrated constitutive expression of ICAM-1 and MHC class I molecules but did not express MHC class II molecules. Basal expression of ICAM-1 molecules was enhanced by TNFα and to a lesser extent by IFN-β, but was not affected by IFN-γ. MHC class I expression on ECs was enhanced by IFN-β, IFN-γ, and tumor necrosis factor (TNF)-α. Furthermore, a synergistic effect was observed to combinations of these interacting cytokines. Incubation of ECs with IFN-γ, but not IFN-β, induced class II expression in a dose dependent manner. Moreover, co-incubation of ECs with IFN-β and IFN-γ resulted in significant down-regulation of class II molecules expression which was directly dependent on IFN-β concentration. Northern blot analysis of DR α and β 2-microglobulin mRNA expression suggested that cytokine-mediated regulation of MHC molecules is at the transcriptional level, while modulation of ICAM-1 expression appears to be at the transcriptional as well as post-transcriptional level. Thus, our study demonstrated that IFN-β and interacting cytokines exert complex immunoregulatory effects on endothelial cells with differential modulatory effects on various cell surface markers. Understanding the biological significance of these immunomodulatory effects mediated by IFN-β may have important implications for cytokine-based strategies in the treatment of inflammatory and autoimmune diseases.