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 mononucl ear cells plays an important role in the generation of or recovery fro m glomerular diseases, We found that cultured mesangial cells secrete a factor that inhibits production of proinflammatory cytokines by acti vated macrophages, Treatment of J774.2 macrophages with conditioned me dia from rat mesangial cells blunted the transcriptional induction of IL-1 beta, IL-6, and TNF-alpha by LPS, None of the media conditioned b y other fibroblastic, epithelial, or endothelial cell lines exhibited the inhibitory effect, Media conditioned by normal rat glomeruli conta ined a similar inhibitory activity, which was enhanced in an acute mod el of mesangial proliferative glomerulonephritis. To identify the acti ve component involved, we examined the expression of known macrophage deactivators IL-10, IL-13, and TGF-beta 1 in mesangial cells, Under th e basal culture conditions, strong expression of TGF-beta 1 mRNA was o bserved, whereas expression of neither IL-10 nor IL-13 was detected, I mmunoblot analysis and a specific bioassay detected the active form of TGF-beta 1 exclusively in the mesangial cell conditioned media, The i nhibitory activity was enhanced by heat treatment, consistent with the known property of TGF-beta. A specific anti-TGF-beta 1 neutralizing A b abolished the inhibitory effect exerted by the mesangial cell media, and exogenously added TGF-beta 1 suppressed macrophage cytokine expre ssion in a dose-dependent manner, These findings demonstrate that mesa ngial cells and isolated glomeruli secrete a factor which suppresses c ytokine expression by activated macrophages, the active entity being i dentified as TGF-beta 1.