Dichotomic effects of IFN‐γ on the development of systemic lupus erythematosus‐like syndrome in MRL‐lpr / lpr mice

Systemic lupus erythematosus (SLE)‐prone female MRL‐lpr / lpr (MRL‐lpr) mice were treated with mouse or rat IFN‐γ under different experimental conditions, both prophylactically in 6‐ to 8 week‐old animals and therapeutically in 12‐ to 18‐week‐old SLE‐affected mice. It was found that IFN‐γ heterogeneously modulated the course of the disease in MRL‐lpr mice. When administered prophylactically, IFN‐γ favorably modulated the histological, serological and clinical signs of the disease. Relative to untreated or PBS‐treated control animals, the MRL‐lpr mice which received IFN γ were virtually free of inflammatory infiltration of the kidneys and the lungs, had lower levels of azotemia with reduction of both circulating IgG1, IgG2a and IgG3 and anti‐double strand (ds) and single strand (ss) DNA antibodies, milder skin vasculitis, significantly reduced enlargment of their lymph nodes and lower weight of the spleens. IFN‐γ also lowered the rate of mortality of MRL‐lpr mice. In contrast to these findings, therapeutically administered IFN‐γ worsened the course of the disease in MRL‐lpr mice, which exhibited increased proteinuria, higher levels of IgG2a and IgG3 and anti‐ds and ‐ss DNA antibodies, more aggressive nephritis and died at an earlier age than PBS‐treated control mice. The dichotomic effect of IFN‐γ on disease manifestation in MRL‐lpr mice offers new insights into the complex role of this cytokine in the regulation of systemic autoimmunity such as SLE.