IL-10 regulates murine lupus

MRL/MpJ-Tnfrsf6^lpr (MRL/MpJ-Fas^lpr; MRL-Fas^lpr) mice develop a spontaneous lupus syndrome closely resembling human systemic lupus erythematosus. To define the role of IL-10 in the regulation of murine lupus, IL-10 gene-deficient (IL-10^-/-) MRL-Fas^lpr (MRL-Fas^lpr IL-10^-/-) mice were generated and their disease phenotype was compared with littermates with one or two copies of an intact IL-10 locus (MRL-Fas^lpr IL-10^+/- and MRL-Fas^lpr IL-10^+/+ mice, respectively). MRL-Fas^lpr IL-10^-/- mice developed severe lupus, with earlier appearance of skin lesions, increased lymphadenopathy, more severe glomerulonephritis, and higher mortality than their IL-10-intact littermate controls. The increased severity of lupus in MRL-Fas^lpr IL-10^-/- mice was closely associated with enhanced IFN-γ production by both CD4⁺ and CD8⁺ cells and increased serum concentration of IgG2a anti-dsDNA autoantibodies. The protective effect of IL-10 in this lupus model was further supported by the observation that administration of rIL-10 reduced IgG2a anti-dsDNA autoantibody production in wild-type MRL-Fas^lpr animals. In summary, our results provide evidence that IL-10 can down-modulate murine lupus through inhibition of pathogenic Th1 cytokine responses. Modulation of the level of IL-10 may be of potential therapeutic benefit for human lupus.