INTERACTION OF IMMUNE-COMPLEXES WITH FC-RECEPTORS IN MESANGIAL CELLS - A POTENTIAL TARGET FOR THE TREATMENT OF IGA NEPHROPATHY

Most human nephritis is caused by the deposition and/or formation of i mmune complexes in the glomerular region. Recently, it has been demons trated that mesangial cells (MC) possess Fc receptors for Ige and IgA. In this work we demonstrate that catabolism of immune complexes occur s via Fc receptors. Mesangial cell incubation with IgA or IgG complexe s induced cell proliferation and extracellular matrix synthesis, two k ey aspects of progressive renal diseases. These effects are in part du e to the production of cytokines IL-6 and transforming growth factor-b eta (TGF-beta), as specific antibodies decreased thymidine incorporati on and fibronectin (FN) production. Fc receptor stimulation induced se veral intracellular signals involving phospholipase C gamma activation , inositol trisphosphate (IP3) formation, and Ca2+ mobilization. Furth ermore, we observed activation of the transcription factor NF-kappa B, and increase in gene expression of monocyte chemoattractant protein-1 (MCP-1), proinflammatory cytokine participating in the recruitment of mononuclear cells, a phenomenon related to the onset and progression of renal injury. These responses depend on the Fc region of immunoglob ulins because Fc fragments inhibited these effects. To observe whether this could be the case in vivo, rats with immune complex nephritis we re treated with IgG-Fc fragments. The administration of fragments sign ificantly decreased proteinuria and morphological lesions. Our results show that MC activation through Fc receptors induces several intracel lular responses, such as cell proliferation, synthesis of proinflammat ory and profibrogenic cytokines, and accumulation of matrix proteins. Modulation of immune complex-MG interaction by in vivo Fc fragments ad ministration could represent a new approach in the glomerulonephritis treatment.