IFN-gamma negatively regulates CpG-induced IL-10 in bone marrow-derived dendritic cells.
Dendritic cells (DCs) are important players in the regulation of Th1- and Th2-dominated immune responses. In these studies we showed that IFN-gamma, the key mediator of Th1 immunity, actively suppressed the production of IL-10 in murine DCs when activated with LPS or CpG. Our analysis revealed that both LPS and CpG induced IL-10 and IL-12 production but that the presence of IFN-gamma, in a dose-dependent manner, suppressed the production of IL-10 while enhancing that of IL-12. The observed inhibition of IL-10 production was independent of IL-12. Experiments performed with STAT-1 knockout mice demonstrated that the primary production of IL-12 induced by CpG was STAT-1 dependent, whereas the production of IL-10 was not. This finding was confirmed by the observation that CpG-induced IL-12 production could be inhibited by anti-IFN-beta Abs, whereas CpG-induced IL-10 production could not be inhibited. These data also demonstrated that the inhibitory effect of IFN-gamma on IL-10 expression was STAT-1 dependent and transcriptionally regulated. Thus, DCs respond to CpG by producing proinflammatory and anti-inflammatory cytokines such as IL-12 and IL-10, respectively, and IFN-gamma acts to not only enhance IL-12 but also to inhibit IL-10 production. The current data demonstrate a novel pathway for IFN-gamma-mediated immunoregulation and suggest that IFN-gamma-dependent suppression of IL-10 production by DCs may be involved in the antagonism between Th1 and Th2 patterns of immune reactivity.
Flores
Rafael R
RR
Department of Immunology and Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Diggs
Kelly A
KA
Tait
Lauren M
LM
Morel
Penelope A
PA
D000818:Animals; D001853:Bone Marrow / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D007371:Interferon-gamma / Q000494:pharmacology* / Q000502:physiology; D016753:Interleukin-10 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D051193:Toll-Like Receptors / Q000819:agonists; D014158:Transcription, Genetic / Q000187:drug effects
C408982:CPG-oligonucleotide; D008024:Ligands; D008070:Lipopolysaccharides; D009838:Oligodeoxyribonucleotides; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D051193:Toll-Like Receptors; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma