Mechanisms underlying the synergistic effect of Th1 cytokines on RANTES chemokine production by human glial cells

RANTES is a β-family chemokine with potent chemoattractant activity for lymphocytes and monocytes that are implicated in the pathogenesis of multiple sclerosis (MS) lesions. Glial cells have been shown to produce RANTES in response to stimulation with Th1 cytokines (IFN-γ, TNF-α, and IL-1β) in vitro, and they may be a major source of RANTES production within diseased brain. This study was undertaken to investigate the mechanism underlying the effect of the Th1 cytokines on the induction of RANTES in a model system for human astroglia. We show that IFN-γ has a synergistic effect with TNF-α or IL-1β on RANTES mRNA and chemokine production in this system. We further show that the combination treatment of IFN-γ and TNF-α, or IFN-γ and IL-1β induced 3-fold higher levels of RANTES gene transcription than seen with either TNF-α or IL-1β alone, as measured by in vitro nuclear transcript elongation assays. In addition, we found that IFN-γ decreased the rate of degradation of RANTES mRNA caused by TNF-α or IL-1β. The t½ of RANTES mRNA was 25±1 h in the presence of both IFN-γ and TNF-α, as compared to a t½ of 15±1 h in the presence of TNF-α alone. This 10 h difference represents an approximate 70% increment in RANTES mRNA half-life. Thus, these results suggest that both increased RANTES gene transcription and increased RANTES mRNA stability may account for the synergistic effect of Th1 cytokines on the up-regulation of RANTES expression in human astroglial cells.