Opposite Regulation of Type II and III Receptors for Immunoglobulin G in Mouse Glomerular Mesangial Cells and in the Induction of Anti-glomerular Basement Membrane (GBM) Nephritis

Abstract We examined the capacity of mouse glomerular mesangial cells (MC) to express and function through two different low affinity FcγRs, the activating FcγRIII and the inhibitory FcγRII. Immunohistochemistry identified FcγRII as the prominent FcγR in the kidney, and low levels of FcγRIIb2-specific mRNA were also detected in primary cultures of growth-arrested MC. Activation by tumor necrosis factor-α/interleukin-1β induced substantial FcγRII expression in proliferating MC. Importantly, however, stimulation with interferon-γ (IFN-γ)/lipopolysaccharide or IFN-γ alone resulted in a complete down-regulation of FcγRII, which was accompanied by a strong increase in FcRγ chain mRNA and a surface appearance of FcγRIII. Activating FcγRIII triggered mRNA synthesis for monocyte chemoattractant protein-1 (MCP-1), MCP-5, cytokine-induced neutrophil chemoattractant, and RANTES, whereas FcγRIII-deficient MC failed to respond to immune complex (IC) activation as shown by impaired production of MCP-1 mRNA/protein. In a passive model of acute anti-glomerular basement membrane (GBM) nephritis, induction of FcγRIII and suppression of FcγRII occurred in kidney tissues. Blockade of FcγRII, when induced selectively in the kidney, resulted in enhanced inflammation. Taken together, our results define a novel regulatory pathway with opposite regulation of FcγRII (suppressed) and FcγRIII (induced) by IFN-γ on MCsin vitro and anti-GBM IgG in vivo. Herein is provided the first evidence that glomerular FcγRII plays an important immunoregulatory role in the initiation of IC glomerulonephritis.