Transforming growth factor-beta 1 is the predominant paracrine inhibitor of macrophage cytokine synthesis produced by glomerular mesangial cells .
Cross-communication between glomerular cells and infiltrating mononuclear cells plays an important role in the generation of or recovery from glomerular diseases. We found that cultured mesangial cells secrete a factor that inhibits production of proinflammatory cytokines by activated macrophages. Treatment of J774.2 macrophages with conditioned media from rat mesangial cells blunted the transcriptional induction of IL-1 beta, IL-6, and TNF-alpha by LPS. None of the media conditioned by other fibroblastic, epithelial, or endothelial cell lines exhibited the inhibitory effect. Media conditioned by normal rat glomeruli contained a similar inhibitory activity, which was enhanced in an acute model of mesangial proliferative glomerulonephritis. To identify the active component involved, we examined the expression of known macrophage deactivators IL-10, IL-13, and TGF-beta 1 in mesangial cells. Under the basal culture conditions, strong expression of TGF-beta 1 mRNA was observed, whereas expression of neither IL-10 nor IL-13 was detected. Immunoblot analysis and a specific bioassay detected the active form of TGF-beta 1 exclusively in the mesangial cell conditioned media. The inhibitory activity was enhanced by heat treatment, consistent with the known property of TGF-beta. A specific anti-TGF-beta 1 neutralizing Ab abolished the inhibitory effect exerted by the mesangial cell media, and exogenously added TGF-beta1 suppressed macrophage cytokine expression in a dose-dependent manner. These findings demonstrate that mesangial cells and isolated glomeruli secrete a factor which suppresses cytokine expression by activated macrophages, the active entity being identified as TGF-beta 1.
Kitamura
M
M
Department of Medicine, University College London Medical School, United Kingdom.
Sütö
T
T
Yokoo
T
T
Shimizu
F
F
Fine
L G
LG
D000818:Animals; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000187:drug effects; D004306:Dose-Response Relationship, Immunologic; D005920:Glomerular Mesangium / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D005921:Glomerulonephritis / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D016212:Transforming Growth Factor beta / Q000096:biosynthesis* / Q000276:immunology / Q000494:pharmacology
D017077:Culture Media, Conditioned; D016207:Cytokines; D008070:Lipopolysaccharides; D016212:Transforming Growth Factor beta