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

AbstractInterferon‐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‐βexposure during naive Th cell stimulation inhibits Th1 cell generation (Nagai et al., J Immunol, 2003171:5233–43). Investigating these contradictory outcomes of IFN‐βexposure, we find that isolated DC matured with both TNF‐αand IFN‐βsecrete more IL‐12 p70 upon CD40L stimulation than DC matured with TNF‐αalone. 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‐γsecretion; 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‐βduring DC maturation, IFN‐βpre‐treatment before CD40L stimulation was found to inhibit IFN‐γ‐mediated enhancement of DC IL‐12 p70 secretion. Thus, IFN‐βexposure during TNF‐α‐mediated DC maturation may promote Th1 polarization by increasing DC IL‐12 p70 secretion, through enhancement of autocrine‐acting IFN‐γproduction by the DC. Moreover, IFN‐βexposure 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‐βpre‐treatment was also observed to inhibit CD40L‐induced DC IL‐23 secretion. Our findings may account for some of the beneficial effects of IFN‐βtherapy in patients with relapsing remitting multiple sclerosis.