title: Expression of transforming growth factor-beta and tumor necrosis factor-alpha in the plasma and tissues of mice with lupus nephritis.
abstract: Although elevated levels of transforming growth factor-beta (TGF-beta) and tumor necrosis factor-alpha (TNF-alpha) 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 lpr/lpr 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-beta and TNF-alpha mRNAs in their kidneys. Although the increase in TGF-beta mRNA was specific for the kidney, the increase in TNF-alpha 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-beta 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-alpha mRNA were detected only in inflammatory cells and were distributed throughout the nephritic kidney. Plasminogen activator inhibitor-1 (PAI-1) is known to be elevated in the glomeruli of MRL lpr/lpr mice, and intraperitoneal administration of either TGF-beta or TNF-alpha 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 PAI-1 may be involved. The fact that TGF-beta is specifically induced in the kidney whereas TNF-alpha increases in a variety of tissues, supports the hypothesis that the renal specificity of this disorder reflects the abnormal expression of TGF-beta.
authors.affiliation: First Department of Internal Medicine, Nagoya University School of Medicine, Japan. kojiy@med.nagoya-u.ac.jp
authors.forename: K
authors.initials: K
authors.lastname: Yamamoto
authors.forename: D J
authors.initials: DJ
authors.lastname: Loskutoff
mesh_terms: D000818:Animals; D005260:Female; D005786:Gene Expression Regulation; D007668:Kidney / Q000378:metabolism; D008181:Lupus Nephritis / Q000378:metabolism*; D051379:Mice; D019463:Mice, Inbred MRL lpr; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis*; D016212:Transforming Growth Factor beta / Q000097:blood / Q000235:genetics* / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000235:genetics* / Q000494:pharmacology
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha