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Glomerular Bioengineering Unit, Department of Medicine, University College London Medical School, London, United Kingdom
Recent investigation has indicated that TGF-ß1, the macrophage
(M
) deactivator, may attenuate M-mediated acute glomerular
injury. Using stromelysin as an indicator, this study investigated
whether and how endogenous TGF-ß1 modulates the glomerular cell
activation triggered by M. Rat mesangial cells were stably
transfected with a cDNA encoding the active form of TGF-ß1 and a cDNA
coding for a dominant-negative mutant of the TGF-ßR type II. Compared
with mock-transfected cells, TGF-ß1 transfectants exhibited blunted
expression of stromelysin in response to the M-derived, inflammatory
cytokine IL-1ß. In contrast, mesangial cells expressing the
dominant-interfering TGF-ßR showed enhanced expression of stromelysin
in response to IL-1ß, suggesting that endogenous TGF-ß functions as
an autocrine inhibitor of the IL-1 response. In isolated, normal rat
glomeruli, externally added TGF-ß1 suppressed the induction of
stromelysin by mediators that were elaborated by activated M.
Similarly, when isolated, nephritic glomeruli producing the active form
of TGF-ß1 were stimulated by IL-1ß or M-conditioned medium, the
induction of stromelysin was dramatically suppressed as compared with
normal glomeruli. To investigate whether endogenous TGF-ß1 affects
the glomerular cell activation triggered by M, a technique for
adoptive M transfer was used. LPS-stimulated reporter M were
transferred into either normal rat glomeruli or nephritic glomeruli
expressing active TGF-ß1. In the normal glomeruli, stromelysin
expression was markedly induced in resident cells after the transfer of
activated M. This induction was substantially repressed in those
glomeruli producing active TGF-ß1. These results reinforce the idea
that TGF-ß1 is an endogenous defender that attenuates certain actions
of infiltrating M in the glomerulus.
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