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IFN- Negatively Regulates CpG-Induced IL-10 in Bone Marrow-Derived Dendritic Cells¹

Department of Immunology and Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261

Dendritic cells (DCs) are important players in the regulation of Th1- and Th2-dominated immune responses. In these studies we showed that IFN-, 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-, 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- Abs, whereas CpG-induced IL-10 production could not be inhibited. These data also demonstrated that the inhibitory effect of IFN- 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- acts to not only enhance IL-12 but also to inhibit IL-10 production. The current data demonstrate a novel pathway for IFN--mediated immunoregulation and suggest that IFN--dependent suppression of IL-10 production by DCs may be involved in the antagonism between Th1 and Th2 patterns of immune reactivity.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant CA73743 (to P.A.M.) and Department of Defense Training Grant DAMD17-99-1-9352 (to R.R.F.). K.A.D. and L.M.T. were supported by a National Science Foundation Research Experiences for Undergraduates Award 0243735.

² Address correspondence and reprint requests to Dr. Penelope A. Morel, Department of Immunology, University of Pittsburgh, Biomedical Science Tower E-1048, 200 Lothrop Street, Pittsburgh, PA 15261. E-mail address: morel{at}pitt.edu

³ Abbreviations used in this paper: DC, dendritic cell; BMDC, bone marrow-derived DC; KO, knockout; WT, wild type; IRF, IFN regulatory factor.

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