IL-12/IL-18-Dependent IFN-γ Release by Murine Dendritic Cells

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Abstract
Dendritic cells (DC) develop in GM-CSF-stimulated cultures from murine bone marrow progenitors in serum-free (or low serum) medium. CD11c+ myeloid DC from 7-day cultures stimulated with TNF-α, IFN-α, IFN-γ, or LPS up-regulated surface expression of CD40 and CD86 costimulator and MHC class II molecules, did not up-regulate the low “spontaneous” release of IL-18, and did not release IFN-γ. Stimulation of in vitro-generated DC with exogenous IL-12 and IL-18 (but not with IL-4 or LPS plus IL-18) induced IFN-γ expression and release in 15–20% of the DC (detectable by FACS analyses or ELISA). Endogenous IL-12 p70 produced by DC in response to ligation of CD40 stimulated IFN-γ release when exogenous IL-18 was supplied. In vivo-generated, splenic CD8α+ and CD8α− DC (from immunocompetent and immunodeficient H-2d and H-2b mice) cultured with IL-12 and IL-18 released IFN-γ. The presence of LPS during the stimulation of DC with IL-18 plus endogenous (CD40 ligation) or exogenous IL-12 did not affect their IFN-γ release. In contrast, splenic DC pretreated in vitro or in vivo by LPS strikingly down-regulated IFN-γ release in response to stimulation by IL-18 and (endogenous or exogenous) IL-12. Hence, DC are a source of early IFN-γ generated in response to a cascade of cytokine- and/or cell-derived signals that can be positively and negatively regulated.