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.
We examined the capacity of mouse glomerular mesangial cells (MC) to express and function through two different low affinity FcgammaRs, the activating FcgammaRIII and the inhibitory FcgammaRII. Immunohistochemistry identified FcgammaRII as the prominent FcgammaR in the kidney, and low levels of FcgammaRIIb2-specific mRNA were also detected in primary cultures of growth-arrested MC. Activation by tumor necrosis factor-alpha/interleukin-1beta induced substantial FcgammaRII expression in proliferating MC. Importantly, however, stimulation with interferon-gamma (IFN-gamma)/lipopolysaccharide or IFN-gamma alone resulted in a complete down-regulation of FcgammaRII, which was accompanied by a strong increase in FcRgamma chain mRNA and a surface appearance of FcgammaRIII. Activating FcgammaRIII triggered mRNA synthesis for monocyte chemoattractant protein-1 (MCP-1), MCP-5, cytokine-induced neutrophil chemoattractant, and RANTES, whereas FcgammaRIII-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 FcgammaRIII and suppression of FcgammaRII occurred in kidney tissues. Blockade of FcgammaRII, when induced selectively in the kidney, resulted in enhanced inflammation. Taken together, our results define a novel regulatory pathway with opposite regulation of FcgammaRII (suppressed) and FcgammaRIII (induced) by IFN-gamma on MCs in vitro and anti-GBM IgG in vivo. Herein is provided the first evidence that glomerular FcgammaRII plays an important immunoregulatory role in the initiation of IC glomerulonephritis.
Radeke
Heinfried H
HH
Department of Clinical Immunology and Institute of Pharmacology, Medical School of Hannover, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany.
Janssen-Graalfs
Iska
I
Sowa
Eveline N
EN
Chouchakova
Nelli
N
Skokowa
Julia
J
Löscher
Fabian
F
Schmidt
Reinhold E
RE
Heeringa
Peter
P
Gessner
J Engelbert
JE
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D019921:Biotinylation; D015139:Blotting, Southern; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D005920:Glomerular Mesangium / Q000276:immunology* / Q000378:metabolism; D007150:Immunohistochemistry; D007668:Kidney / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009393:Nephritis / Q000378:metabolism; D009504:Neutrophils; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017452:Receptors, IgG / Q000737:chemistry*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012260:Ribonucleases / Q000378:metabolism
D000911:Antibodies, Monoclonal; D018932:Chemokine CCL2; D012333:RNA, Messenger; D017452:Receptors, IgG; D012313:RNA; D012260:Ribonucleases