Suto, Tamas Sandor; (1999) Glomerular self-defence : A role of mesangial cell-derived transforming growth factor - β. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Communication between resident glomerular cells and infiltrating macrophages via paracrine mediators plays a crucial role in the pathogenesis of glomerular disease. However, the precise manner of in vivo cross-talk between macrophages and glomerular cells remains unclear. The aim of the present studies is to elucidate the role of mesangial cells in the regulation of macrophage function. Mesangial cells were found to secrete factors that impair function of macrophages, and transforming growth factor-l (TGF-β1) was identified as one of the mesangial cell-derived molecules involved in this process. Mesangial cell-derived TGF-β1 reduced macrophage adhesiveness and caused consequent deactivation. Mesangial cell-derived TGF-β1 also inhibited production of proinflammatory cytokines by activated macrophages. It was hypothesised that, in certain inflammatory situations, mesangial cell-derived TGF-β1 may function as a defender against macrophage-mediated glomerular injury. To examine this possibility, a technique for in vivo macrophage transfer was developed. Lipopolysaccharide-stimulated reporter macrophages were transferred into normal rat glomeruli or nephritic glomeruli producing active TGF-β1. In the normal glomeruli, expression of activation markers (gelatinase B, inducible nitric oxide synthase, stromelysin) were induced in resident cells after the transfer of activated macrophages. In contrast, this induction was substantially repressed in the regenerating glomeruli that produced active TGF-βl. These results point to an intrinsic potential of mesangial cell-derived TGF-β1 to suppress the macrophage-initiated glomerular cell activation. TGF-β1 may be regarded as a possible, endogenous defender that attenuates the action of infiltrating macrophages in the glomerulus.

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