Differential Effects of IFNβ on IL-12, IL-23, and IL-10 Expression in TLR-stimulated Dendritic Cells (BA7P.157)

Abstract Autoimmune disease multiple sclerosis (MS) is characterized by immune cell infiltration in the CNS leading to cumulative disability. IFNβ, used clinically in remitting-relapsing MS, reduces lesion formation and rate of relapses. Although the molecular mechanisms are not entirely elucidated, myeloid cells appear to be a major target for the therapeutic effects of IFNβ. Dendritic cells (DC) play a critical role in experimental models of MS, through their effect on Th1/Th17 cell differentiation and expansion. Here we studied the effects of IFNβ on DC expression of cytokines involved in Th1/Th17 differentiation. Administration of IFNβ to EAE mice inhibited IL-12 and IL-23 expression in splenic DC and reduced in vivo differentiation of Th1/Th17 cells. IFNβ affected cytokine expression in TLR-stimulated DC in a similar manner in vitro, inhibiting IL-12 and IL-23 and stimulating IL-10 at both mRNA and protein levels, by signaling through IFNAR. We investigated the role of the signaling molecules STAT1/STAT2, IRF1 and IRF7, and of the PI3KàGSK3 pathway. Inhibition of IL-12 p40 and p35 by IFNβ was mediated through STAT1/STAT2, whereas inhibition of IL-23 was STAT1-depedent, and the stimulatory effect on IL-10 expression was mediated through STAT2. Although IFNβ induces IRF-7 and IRF-1, neither IRF mediated the effects of IFNβ on IL-12, IL-23, or IL-10. We found that the PI3K pathway mediated IL-12 inhibition but did not interfere with the inhibition of IL-23 or stimulation of IL-10.