Receptors for immune complexes activate gene expression and synthesis of matrix proteins in cultured rat and human mesangial cells: role of TGF-beta.
Most human glomerulonephritis are induced by the deposition and/or formation of immune complexes in the glomerular region. Recently, it has been demonstrated that cultured glomerular mesangial cells (MC) express Fc receptors for IgA and IgG (Fc-alpha and Fc-gamma receptors). In this work, we studied whether the interaction of IgA and IgG complexes with MC induces accumulation of mesangial matrix, the histologic hallmark of progressive glomerular diseases. The exposure of MC to IgA and IgG complexes increased extracellular matrix components, such as fibronectin (FN) and collagens, at both the mRNA and protein levels in a time- and dose-dependent manner. Monomeric IgA or F(ab')2 fragments did not increase FN production, indicating that a constant region of IgA and cross-linking of Fc-alpha receptors are required. We also explored the role of TGF-beta, a profibrogenic cytokine, in the regulation of matrix synthesis. Both IgA and IgG complexes caused in MC an augmentation in TGF-beta1 mRNA and TGF-beta activity and the conversion of latent TGF-beta to the biologically active form. The coincubation of cells with complexes and a neutralizing Ab to TGF-beta significantly reduced the FN synthesis. These results indicate that the Fc receptor occupancy of MC increases the production of extracellular matrix proteins. The autocrine TGF-beta synthesis appears to be largely responsible for this effect. These findings could have implications for a better understanding of the glomerulosclerosis process in immune complex nephritis.
López-Armada
M J
MJ
Renal Research Laboratory, Jiménez Díaz Foundation, Autonomous University, Madrid, Spain.
Gómez-Guerrero
C
C
Egido
J
J
D000818:Animals; D000936:Antigen-Antibody Complex / Q000378:metabolism*; D002478:Cells, Cultured; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis* / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology*; D005920:Glomerular Mesangium / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D007070:Immunoglobulin A / Q000494:pharmacology; D007074:Immunoglobulin G / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011971:Receptors, Immunologic / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology*
D000936:Antigen-Antibody Complex; D016326:Extracellular Matrix Proteins; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D011971:Receptors, Immunologic; D016212:Transforming Growth Factor beta