Interferon-beta mediates opposing effects on interferon-gamma-dependent Interleukin-12 p70 secretion by human monocyte-derived dendritic cells.
Interferon-beta (IFN-beta) exposure during tumour necrosis factor-alpha (TNF-alpha)-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-beta 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-beta exposure, we find that isolated DC matured with both TNF-alpha and IFN-beta secrete more IL-12 p70 upon CD40L stimulation than DC matured with TNF-alpha 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-gamma secretion; and (2) an IFN-gamma-initiated autocrine pathway promoting optimal DC IL-12 p70 secretion. In contrast to the IL-12 p70 promoting effects of IFN-beta during DC maturation, IFN-beta pre-treatment before CD40L stimulation was found to inhibit IFN-gamma-mediated enhancement of DC IL-12 p70 secretion. Thus, IFN-beta exposure during TNF-alpha-mediated DC maturation may promote Th1 polarization by increasing DC IL-12 p70 secretion, through enhancement of autocrine-acting IFN-gamma production by the DC. Moreover, IFN-beta exposure during naive Th cell stimulation may inhibit Th1 cell generation by blocking the IFN-gamma-induced signals required for optimal CD40L-induced DC IL-12 p70 secretion. IFN-beta 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-beta therapy in patients with relapsing remitting multiple sclerosis.
Nagai
T
T
Department of Environmental Health, Boston University School of Public Health, Boston, MA 02118, USA.
Devergne
O
O
van Seventer
G A
GA
van Seventer
J M
JM
D023201:CD40 Ligand / Q000494:pharmacology; D016764:Cell Polarity; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D016899:Interferon-beta / Q000494:pharmacology*; D007371:Interferon-gamma / Q000378:metabolism* / Q000494:pharmacology; D018664:Interleukin-12 / Q000378:metabolism*; D020382:Interleukin-18 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D009000:Monocytes / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D020382:Interleukin-18; D007378:Interleukins; C464565:MYDGF protein, human; D014409:Tumor Necrosis Factor-alpha; D023201:CD40 Ligand; D018664:Interleukin-12; D016899:Interferon-beta; D007371:Interferon-gamma