Expression of transforming growth factor-β and tumor necrosis factor-α in the plasma and tissues of mice with lupus nephritis

Abstract

Although elevated levels of transforming growth factor-β (TGF-β) and tumor necrosis factor-α (TNF-α) have been implicated in renal disease, the tissue distribution and cellular localization of the induced cytokines is not well established. In this study, we investigated the expression of these cytokines during the progression of lupus nephritis in MRL Ipr/Ipr mice. The concentration of both cytokines increased in the plasma of these animals in an age-dependent manner, and there was an age-dependent induction of TGF-β and TNF-α mRNAs in their kidneys. Although the increase in TGF-β mRNA was specific for the kidney, the increase in TNF-α mRNA was widespread and also could be demonstrated in the liver, lung, and heart. In situ hybridization analysis of renal tissues from the lupus-prone mice localized TGF-β mRNA to the glomerulus, and more specifically, to resident glomerular cells and inflammatory cells infiltrating periglomerular spaces in the nephritic lesions. The signals for TNF-α mRNA were detected only in inflammatory cells and were distributed throughout the nephritic kidney. Plasminogen activator inhibitor-1 (PAl-1) is known to be elevated in the glomeruli of MRL Ipr/Ipr mice, and intraperitoneal administration of either TGF-β or TNF-α into normal mice markedly induced the expression of this potent inhibitor of fibrinolysis in renal glomerular or tubular cells in vivo. These results suggest that the increased renal expression of both cytokines may contribute to the development of lupus nephritis in this model and raise the possibility that PAl-1 may be involved. The fact that TGF-β is specifically induced in the kidney whereas TNF-α increases in a variety of tissues, supports the hypothesis that the renal specificity of this disorder reflects the abnormal expression of TGF-β.