IFNβ: an anti-inflammatory cytokine which inhibits dendritic cell migration and proinflammatory cytokine production (35.1)

Abstract

Abstract IFNβ is an approved therapeutic option for the treatment of autoimmune disease, MS/EAE. However, the molecular mechanisms underlying the effects of IFNβ in MS/EAE are not fully understood. In EAE, migrating CD4+ T cells and dendritic cells (DC) are essential for development of clinical symptoms. Expressions of CCR7 and MMP-9 are required for DC migration from the inflammatory site to draining lymph nodes for antigen presentation and activation of naïve T cells and to the CNS during chronic neuroinflammation. Our results show IFNβ inhibits CCR7 expression, MMP-9 production, and migration of DCs matured with different stimuli, including LPS, Poly I:C, TNFα+IFNα, or TNFα+IL-1β+IL-6 in the presence of PGE2. STAT-1 activation is required for the IFNβ-mediated inhibition of CCR7 and MMP-9 expression, and subsequent DC migration. In addition, IFNβ inhibits the production of the proinflammatory cytokines IL-12 and IL-23, whereas promoting the expression of the antinflammatory cytokine IL-10. In vivo administration of IFNβ results in doneregulation of CCR7 and MMP-9 expression, while upregulation of IL-10 production in splenic CD11c+ DC. There is reduced in vivo migration of exogenous DC treated with IFNβ, and of endogenous DC exposed to FITC in mice inoculated with IFNβ. In conclusion, our results provide novel molecular mechanisms for the beneficial effects of IFNβ in MS/EAE through the inhibition of mature DC migration and proinflammtory cytokine production.