TGF-beta1 as an endogenous defender against macrophage-triggered stromelysin gene expression in the glomerulus

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.