IFN-γ induces the high-affinity Fc receptor I for IgG (CD64) on human glomerular mesangial cells

Abstract

The deposition of immune complexes, followed by activation of complement and/or Fc receptors and generation of chemoattractants, is the most common feature of human glomerulonephritis. Recently we have shown that primary cultured human glomerular mesangial cells (HMC), which are normally negative for IgG Fc receptors, can be stimulated to express the low-affinity FcgammaRIII-A receptor isoform. In this study we further demonstrate that activation of HMC through IFN-gamma resulted in the functional expression of the high-affinity Fc receptor for IgG (FcgammaRI, CD64). IFN-gamma-dependent induction of classical FcgammaRIa1 mRNA as well as a2, b2 splice variants were evident after 24 h in proliferating HMC and after 48 h in resting HMC. Transcription of FcgammaRI mRNA was also induced by IL-10 in proliferating HMC, whereas other cytokines such as IL-3, transforming growth factor-beta1 and granulocyte-macrophage colony-stimulating factor were not effective. Cell surface expression of FcgammaRI could be detected by flow cytometric analysis after IFN-gamma stimulation and was accompanied by the augmentation of MHC class II and the up-regulation of intercellular adhesion molecule-1 expression. Triggering of HMC by cross-linking FcgammaRI with F(ab')2 fragments of the anti-CD64 monoclonal antibody 22 led to enhanced synthesis of mRNA for the chemokines IL-8 and monocyte chemoattractant protein-1, indicating that the FcgammaRI of HMC is functionally active. These in vitro data suggest that engagement of both FcgammaRI and FcgammaRIII-A on activated HMC through IgG immune complexes may result in an increased chemoattraction of leukocytes into the glomerulus, contributing to the development of glomerulonephritis.

IFNγ induces functional chemokine receptor expression in human mesangial cells

“…So far there are only a few reports describing the expression of chemokine receptors and their distinct functions in non-haematopoietic tissue cells, including glomerular mesangial cells [18][19][20][21]. To extend knowledge of the role of chemokines in glomerular inflammation, we investigated the expression of chemokine receptors and their functions in our well established primary human mesangial cell (HMC) culture system [1,7,8,13]. There is evidence that chemokine receptor expression in leucocytes can be regulated by inflammatory signals such as gamma-interferon (IFNg) and interleukins (IL) [22,23].…”

“…Pathobiological responses of mesangial cells to inflammatory stimuli often initiate and maintain pathogenic processes within the glomerulus. They seem to participate in the majority of forms of glomerulonephritis (GN), acting as inflammatory cells by generating nitrite and oxygen radicals [4], prostaglandins [1,5] and extracellular matrix components [6], or by up-regulating the expression of surface molecules, especially Fc receptors for IgG [7,8], MHC class II and adhesion proteins [9]. A characteristic feature of GN is the infiltration of leucocytes from the circulation into the kidney tissue, and the subsequent activation of such inflammatory cells at the site of glomerular injury.…”

Expression of a Functional High-Affinity IgG Receptor, FcγRI, on Human Mast Cells: Up-Regulation by IFN-γ

“…Fc⑀RI binds monomeric IgE with a K a of 10 10 M Ϫ1 , is expressed with ␣-, ␤-, and ␥-chains on mast cells and basophils (1,3,4) and is believed in humans to essentially be responsible for allergendependent allergic responses; thus, the focus on the identification of Ag-specific IgE in the evaluation of the patient with an allergic reaction (4). Fc␥RI, which binds monomeric IgG with a K a of 10 8 -10 9 M Ϫ1 , is reported to be expressed by monocytes, macrophages, and IFN-␥-stimulated neutrophils, eosinophils, and glomerular mesangial cells (1)(2)(3)5). This receptor is believed to mediate phagocytosis, Ab-dependent cellular cytotoxicity, superoxide production, Ag presentation, and cytokine release (1)(2)(3)5).…”

“…Fc␥RI, which binds monomeric IgG with a K a of 10 8 -10 9 M Ϫ1 , is reported to be expressed by monocytes, macrophages, and IFN-␥-stimulated neutrophils, eosinophils, and glomerular mesangial cells (1)(2)(3)5). This receptor is believed to mediate phagocytosis, Ab-dependent cellular cytotoxicity, superoxide production, Ag presentation, and cytokine release (1)(2)(3)5).…”

TLR3-dependent immune regulatory functions of human mesangial cells

“…Particularly in glomerulonephritides that involve locally deposited immune complexes with a corresponding activation of complement, this hypothesis is substantiated by the observation of a concomitant induction of MHC class II molecules, ICAM-1 and complement receptors in human MC by interferon gamma. 33 This specific etiology needs further attention. …”