IN-VIVO TRANSFER OF ENGINEERED MACROPHAGES INTO THE GLOMERULUS - ENDOGENOUS TGF-BETA-MEDIATED DEFENSE AGAINST MACROPHAGE-INDUCED GLOMERULARCELL ACTIVATION

Communication between resident glomerular cells and infiltrating macro phages plays a crucial role in the pathogenesis of glomerular disease, Using matrix metalloproteinase-9 (MMP-9) as an indicator molecule, we examined the interaction between mesangial cells and macrophages, Mes angial cells cocultured with activated macrophages or exposed to macro phage-conditioned media produced abundant MMP-9, We identified the sti mulator secreted by macrophages as IL-1 because mesangial cells overex pressing IL-1 receptor antagonist protein showed a blunted expression of MMP-9 in response to the macrophage-conditioned medium, In contrast , culture supernatants of mesangial cells inhibited MMP-9 production b y macrophages in a dose-dependent fashion, This inhibitor was identifi ed to be TGF-beta 1, since neutralization of TGF-beta 1 abrogated the inhibitory effect of the mesangial cell-conditioned medium, To investi gate whether activated macrophages induce glomerular MMP-9 expression, and if so, how endogenous TGF-beta 1 modulates the induction, stimula ted reporter macrophages were transferred into normal rat glomeruli or glomeruli in the regeneration phase of acute anti-Thy-1. glomerulonep hritis. In the normal glomeruli, MMP-9 expression was up-regulated in resident cells after the transfer of activated macrophages. This induc tion was substantially repressed in the regenerating glomeruli that pr oduced active TGF-beta 1, These results point to potential mechanisms involved in glomerular control of MMP-9, Based upon the in vitro evide nce, TGF-beta 1 was identified as an endogenous ''defender'' that atte nuates certain actions of infiltrating macrophages in the glomerulus.