Ifi202, an IFN-inducible candidate gene for lupus susceptibility in NZB/ W F1 mice, is a positive regulator for NF-κB activation in dendritic cells

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the presence of autoantibodies and lupus nephritis. The [New Zealand black (NZB) × New Zealand white (NZW)]F1 (BWF1) mouse has been recognized as an important animal model of human SLE. The T_h1-prone phenotype of BWF1 mice has been shown to contribute to the development of the lupus. However, the molecular basis for T_h1 skewing in BWF1 mice has not been clarified. We noticed that IL-6, IL-12 and other proinflammatory cytokines as well as IκB-ζ induction were higher in mature bone marrow-derived dendritic cells (BMDCs) from NZB and BWF1 mice than those from NZW mice. The expression of an IFN-inducible gene Ifi202, a candidate gene for lupus, was almost undetectable in NZW BMDCs. Thus, we hypothesized that Ifi202 is involved in elevated IL-12 production from BWF1 BMDCs. Overexpression of Ifi202 enhanced the LPS-induced IκB-ζ, IL-12p40 and NF-κB promoter activities, while anti-sense (AS) RNA against Ifi202 strongly suppressed them in a monocytic cell line, RAW 264.7. Furthermore, overexpression of Ifi202 enhanced LPS-induced IL-12p40 and IκB-ζ mRNA induction while Ifi202 AS RNA suppressed these in RAW 264.7 cells. In addition, forced expression of Ifi202 enhanced IL-12p40 mRNA induction in NZW BMDCs. Thus, Ifi202 is an important NF-κB activator in DCs and involved in IL-12 production, which may account for a T_h1-prone phenotype of BWF1 mice.