CYTOKINE GENE-EXPRESSION IN THE MRL LPR MODEL OF LUPUS NEPHRITIS/

The murine MRL/lpr model of lupus nephritis is characterized by a syst emic autoimmune syndrome closely resembling the human disease. The lpr mutation represents a defect in the expression of the apoptosis-signa ling Fas antigen gene which causes accelerated autoimmune disease in M RL/lpr mice and a milder, non-lethal autoimmune syndrome in C57BL6-lpr /lpr mice. The role of cytokines in autoimmune pathogenesis and its re lationship with the lpr mutation remains poorly understood. In this st udy we utilized a RNase protection assay to quantitatively and simulta neously examine the expression of 10 different cytokine genes, namely IL-1 alpha, IL-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, IFN-gamma, TNF-al pha, and TNF-beta in kidney; spleen, liver, and lymph nodes obtained f rom 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 B alb/c mice. Diseased MRL/lpr mice demonstrated marked and predominant IL-1 beta gene upregulation in kidneys, liver, lymph nodes and spleen. Increased message for both TNF-alpha and IFN-gamma genes was also obs erved in lymph nodes, and less consistently, in the spleen, and kidney s derived from diseased MRL/lpr mice as compared to pre-diseased MRL/+ or normal nonautoimmune control mice. Furthermore, a modest increase in the expres sion of both IL-1 beta and IFN-gamma message was observ ed in lymphoid organs of pre-diseased MRL/lpr and C57BL/6-lpr mice com pared with MRL/++ and C57BL/6 controls, respectively. Increased IL-1 b eta gene expression was associated with the presence of the lpr mutati on, was observed during the prediseased stage, and increased during ac tive disease in both male and female mice. In summary, these results d emonstrate that generalized up-regulation of IL-1 beta gene expression , in concert with a more limited up-regulation of both TNF-alpha and I FN-gamma expression, are prominent features of the autoimmune syndrome in the MRL/lpr model of SLE and may contribute to the disease-acceler ating effect of the lpr mutation.