Type I interferons are associated with lupus. Genes that are regulated by IFN- (cid:2) are upregulated in pediatric lupus patients. Gene deletion of the IFN- (cid:2) / (cid:1) receptor in experimental lupus-like NZB mice results in reduced disease activity. Conversely, IFN- (cid:1) is a well-established treatment in multiple sclerosis, another autoimmune disease. For determining whether IFN- (cid:1) treatment is harmful or beneficial in lupus, MRL- Fas lpr mice were injected with this type I IFN. Treatment was initiated in MRL- Fas lpr mice with mild and advanced disease. IFN- (cid:1) was highly effective in prolonging survival and ameliorating the clinical (renal function, proteinuria, splenomegaly, and skin lesions), serologic (autoantibodies and cytokines), and histologic parameters of the lupus-like disease in mice that had mild and advanced disease. Several underlying mechanisms of IFN- (cid:1) therapy involving cellular (decreased T cell proliferation and infiltration of leukocytes into the kidney) and humoral (decrease in IgG3 isotypes) immune responses and a reduction in nephrogenic cytokines were identified. In conclusion, IFN- (cid:1) treatment of lupus nephritis in MRL- Fas lpr mice is remarkably beneficial and suggests that IFN- (cid:1) may be an appealing therapeutic candidate for subtypes of human lupus. denaturing polyacrylamide gels, by autoradiography. treatment were analyzed and quantified using densitometry rela-tive to the housekeeping genes. phorbolmyristate acetate (PMA), and TNF- (cid:6) in the presence or absence of IFN- (cid:1) overnight. Tubular epithelial (TEC) were for 24 h before stimulation with IFN- (cid:2) or nephritic serum in the presence or absence of IFN- (cid:1) . After addition of 10 (cid:3) l/well of the MTT-salt solution and incubation at 37°C for 4 h, 100 (cid:3) l/well of the solubilization solution was added and kept in the incubator overnight. We measured the absorption with an ELISA reader at (cid:5) (cid:2) nm. In addition to the MTT proliferation assay, the thymidine proliferation assay performed, as recently described (25).