Systemic lupus erythematosus (SLE) is a polyclonal autoimmune syndrome directed against multiple nuclear
autoantigens. Although
RNA and
DNA seem to have identical immunostimulatory effects on systemic and intrarenal
inflammation, each seems to differ with regard to the propensity to induce mitogenic effects such as lymphoproliferation. To identify potential mechanisms by which
DNA specifically contributes to the pathogenesis of
lupus nephritis, we stimulated cells with immunostimulatory
DNA or
RNA in vitro and used microarray to compare the transcriptomes of
RNA- and
DNA-induced genes. Immunostimulatory
DNA, but not
RNA, induced Mdm2, which is a negative regulator of p53. In vivo, we observed greater expression and activation of Mdm2 in the spleen and kidneys in a mouse model of lupus (MRL-Fas(lpr) mice) than healthy controls. Treatment of MRL-Fas(lpr) mice with the Mdm2 inhibitor
nutlin-3a prevented
nephritis and
lung disease and significantly prolonged survival. Inhibition of Mdm2 reduced systemic
inflammation and abrogated
immune complex disease by suppressing plasma cells and the production of lupus
autoantibodies. In addition,
nutlin-3a suppressed the abnormal expansion of all T cell subsets, including CD3(+)CD4(-)CD8(-) T cells, which associated with attenuated systemic
inflammation. However, inhibiting Mdm2 did not cause myelosuppression or affect splenic regulatory T cells, neutrophils, dendritic cells, or monocytes. Taken together, these data suggest that the induction of Mdm2 promotes the expansion of plasma cells and CD3(+)CD4(-)CD8(-) T cells, which cause
autoantibody production and
immune complex disease in MRL-Fas(lpr) mice. Antagonizing Mdm2 may have therapeutic potential in
lupus nephritis.