Cytokine gene expression in the MRL/lpr model of lupus nephritis

Cytokine gene expression in the MRL/lpr model of lupus nephritis. The murine MRL/lpr model of lupus nephritis is characterized by a systemic autoimmune syndrome closely resembling the human disease. The lpr mutation represents a defect in the expression of the apoptosis-signaling Fas antigen gene which causes accelerated autoimmune disease in MRL/lpr mice and a milder, non-lethal autoimmune syndrome in C57BL6-lpr/lpr mice. The role of cytokines in autoimmune pathogenesis and its relationship with the lpr mutation remains poorly understood. In this study we utilized a RNase protection assay to quantitatively and simultaneously examine the expression of 10 different cytokine genes, namely IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IFN-γ, TNF-α, and TNF-β in kidney, spleen, liver, and lymph nodes obtained from pre-diseased and diseased lupus-prone MRL/lpr, pre-diseased MRL/+ + and C57BL/6-lpr mice, as well as healthy non-autoimmune C57BL/6 and Balb/c mice. Diseased MRL/lpr mice demonstrated marked and predominant IL-1β gene up-regulation in kidneys, liver, lymph nodes and spleen. Increased message for both TNF-α and IFN-γ genes was also observed in lymph nodes, and less consistently, in the spleen, and kidneys derived from diseased MRL/lpr mice as compared to pre-diseased MRL/+ + or normal non-autoimmune control mice. Furthermore, a modest increase in the expression of both IL-1β and IFN-γ message was observed in lymphoid organs of pre-diseased MRL/lpr and C51BL/6-lpr mice compared with MRL/+ + and C57BL/6 controls, respectively. Increased IL-1β gene expression was associated with the presence of the lpr mutation, was observed during the prediseased stage, and increased during active disease in both male and female mice. In summary, these results demonstrate that generalized up-regulation of IL-1β gene expression, in concert with a more limited up-regulation of both TNF-α and IFN-γ expression, are prominent features of the autoimmune syndrome in the MRL/lpr model of SLE and may contribute to the disease-accelerating effect of the lpr mutation