title: TGF-beta1 as an endogenous defender against macrophage-triggered stromelysin gene expression in the glomerulus.
abstract: Recent investigation has indicated that TGF-beta1, the macrophage (Mphi) deactivator, may attenuate Mphi-mediated acute glomerular injury. Using stromelysin as an indicator, this study investigated whether and how endogenous TGF-beta1 modulates the glomerular cell activation triggered by Mphi. Rat mesangial cells were stably transfected with a cDNA encoding the active form of TGF-beta1 and a cDNA coding for a dominant-negative mutant of the TGF-betaR type II. Compared with mock-transfected cells, TGF-beta1 transfectants exhibited blunted expression of stromelysin in response to the Mphi-derived, inflammatory cytokine IL-1beta. In contrast, mesangial cells expressing the dominant-interfering TGF-betaR showed enhanced expression of stromelysin in response to IL-1beta, suggesting that endogenous TGF-beta functions as an autocrine inhibitor of the IL-1 response. In isolated, normal rat glomeruli, externally added TGF-beta1 suppressed the induction of stromelysin by mediators that were elaborated by activated Mphi. Similarly, when isolated, nephritic glomeruli producing the active form of TGF-beta1 were stimulated by IL-1beta or Mphi-conditioned medium, the induction of stromelysin was dramatically suppressed as compared with normal glomeruli. To investigate whether endogenous TGF-beta1 affects the glomerular cell activation triggered by Mphi, a technique for adoptive Mphi transfer was used. LPS-stimulated reporter Mphi were transferred into either normal rat glomeruli or nephritic glomeruli expressing active TGF-beta1. In the normal glomeruli, stromelysin expression was markedly induced in resident cells after the transfer of activated Mphi. This induction was substantially repressed in those glomeruli producing active TGF-beta1. These results reinforce the idea that TGF-beta1 is an endogenous defender that attenuates certain actions of infiltrating Mphi in the glomerulus.
authors.affiliation: Department of Medicine, University College London Medical School, United Kingdom. m.kitamura@medicine.ucl.ac.uk
authors.forename: M
authors.initials: M
authors.lastname: Kitamura
mesh_terms: D000818:Animals; D015870:Gene Expression; D007375:Interleukin-1 / Q000494:pharmacology; D007678:Kidney Glomerulus / Q000378:metabolism*; D008264:Macrophages / Q000502:physiology*; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016212:Transforming Growth Factor beta / Q000502:physiology*
chemical_list: D007375:Interleukin-1; D016212:Transforming Growth Factor beta; D019278:Matrix Metalloproteinase 3