Intrinsic Interferon Signature in Dendritic Cells in lupus-prone mice. (83.9)

Abstract

Abstract Type I Interferons (IFNs) are pathogenic in Systemic Lupus Erythematosus. PBMCs from lupus patients over-express Type I IFN responsive genes. The cause and cellular source of this "Interferon Signature" are still unclear. Since we found that dendritic cells (DCs) from lupus-prone mice express the IFN Signature, we asked whether this IFN Signature was intrinsic to the DCs. We found that bone marrow-derived dendritic cells (BMDCs) from young pre-diseased Sle1,2,3 lupus-prone mice constitutively over-express Type I IFN responsive genes, analyzed by real-time RT-PCR (IFN-a, IFN-b, STAT1, STAT2, Mx1, IL-6, IL-15, IRF-7), as compared to autoimmune C57BL/6 BMDCs, as well as ELISA and flow cytometry. We also found that STAT1 is constitutively phosphorylated, suggesting an ongoing response to Type I IFN in the Sle1,2,3 DCs. Treatment with ligands for TLR7 and TLR9 showed that lupus BMDCs are hyper-sensitive to nucleic acids. To determine the mechanism of the constitutive hyper-activation of the IFN response in lupus DCs, we treated Sle1,2,3 BMDCs with inhibitors of TLR7 and TLR9 and found a partial role for chronic exposure to nucleic acids. We are now testing other mechanisms to explain the IFN Signature in lupus DCs. We have reported earlier that IL-4 suppresses Type I IFN responses in DCs of normal mice. We have now found that IL-4 inhibits the IFN Signature in Sle1,2,3 BMDCs, suggesting IL-4 as a potential therapeutic strategy for lupus by suppressing the Type I IFN effects.