title: In vivo transfer of engineered macrophages into the glomerulus: endogenous TGF-beta-mediated defense against macrophage-induced glomerular cell activation.
abstract: Communication between resident glomerular cells and infiltrating macrophages 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. Mesangial cells cocultured with activated macrophages or exposed to macrophage-conditioned media produced abundant MMP-9. We identified the stimulator secreted by macrophages as IL-1 because mesangial cells overexpressing 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 by macrophages in a dose-dependent fashion. This inhibitor was identified to be TGF-beta1, since neutralization of TGF-beta1 abrogated the inhibitory effect of the mesangial cell-conditioned medium. To investigate whether activated macrophages induce glomerular MMP-9 expression, and if so, how endogenous TGF-beta1 modulates the induction, stimulated reporter macrophages were transferred into normal rat glomeruli or glomeruli in the regeneration phase of acute anti-Thy-1 glomerulonephritis. In the normal glomeruli, MMP-9 expression was up-regulated in resident cells after the transfer of activated macrophages. This induction was substantially repressed in the regenerating glomeruli that produced active TGF-beta1. These results point to potential mechanisms involved in glomerular control of MMP-9. Based upon the in vitro evidence, TGF-beta1 was identified as an endogenous "defender" that attenuates certain actions of infiltrating macrophages in the glomerulus.
authors.affiliation: Department of Medicine, University College London Medical School, United Kingdom.
authors.forename: T S
authors.initials: TS
authors.lastname: Sütö
authors.forename: L G
authors.initials: LG
authors.lastname: Fine
authors.forename: F
authors.initials: F
authors.lastname: Shimizu
authors.forename: M
authors.initials: M
authors.lastname: Kitamura
mesh_terms: D000818:Animals; D015415:Biomarkers; D002450:Cell Communication; D002465:Cell Movement; D002478:Cells, Cultured; D018920:Coculture Techniques; D017364:Collagenases / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D017077:Culture Media, Conditioned; D004790:Enzyme Induction / Q000187:drug effects; D017930:Genes, Reporter; D005920:Glomerular Mesangium / Q000166:cytology* / Q000378:metabolism; D005921:Glomerulonephritis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism / Q000502:physiology*; D008297:Male; D020780:Matrix Metalloproteinase 9; D051381:Rats; D017207:Rats, Sprague-Dawley; D012795:Sialoglycoproteins / Q000378:metabolism; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000502:physiology*; D001616:beta-Galactosidase / Q000032:analysis
chemical_list: D015415:Biomarkers; D017077:Culture Media, Conditioned; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D012795:Sialoglycoproteins; D016212:Transforming Growth Factor beta; D001616:beta-Galactosidase; D017364:Collagenases; D020780:Matrix Metalloproteinase 9