Interferon‐ β Mediates Opposing Effects on Interferon‐ γ ‐dependent Interleukin‐12 p70 Secretion by Human Monocyte‐Derived Dendritic Cells

Interferon‐ β (IFN‐ β ) exposure during tumour necrosis factor‐ α (TNF‐ α )‐induced human monocyte‐derived dendritic cell (DC) maturation augments the capacity of DC to promote the generation of T helper 1 (Th1) cells, while IFN‐ β exposure during naive Th cell stimulation inhibits Th1 cell generation (Nagai et al., J Immunol, 2003 171 :5233–43). Investigating these contradictory outcomes of IFN‐ β exposure, we find that isolated DC matured with both TNF‐ α and IFN‐ β secrete more IL‐12 p70 upon CD40L stimulation than DC matured with TNF‐ α alone. mAb blocking studies indicate that the basis for this enhanced IL‐12 p70 production is augmentation of two successive CD40‐dependent autocrine pathways in the DC: (1) a pathway in which low levels of IL‐12 p70, IL‐27, IL‐18 and, possibly, IL‐23 act to mediate autocrine induction of DC IFN‐ γ secretion; and (2) an IFN‐ γ ‐initiated autocrine pathway promoting optimal DC IL‐12 p70 secretion. In contrast to the IL‐12 p70 promoting effects of IFN‐ β during DC maturation, IFN‐ β pre‐treatment before CD40L stimulation was found to inhibit IFN‐ γ ‐mediated enhancement of DC IL‐12 p70 secretion. Thus, IFN‐ β exposure during TNF‐ α ‐mediated DC maturation may promote Th1 polarization by increasing DC IL‐12 p70 secretion, through enhancement of autocrine‐acting IFN‐ γ production by the DC. Moreover, IFN‐ β exposure during naive Th cell stimulation may inhibit Th1 cell generation by blocking the IFN‐ γ ‐induced signals required for optimal CD40L‐induced DC IL‐12 p70 secretion. IFN‐ β pre‐treatment was also observed to inhibit CD40L‐induced DC IL‐23 secretion. Our findings may account for some of the beneficial effects of IFN‐ β therapy in patients with relapsing remitting multiple sclerosis.