Interaction of IgA with Fc alpha receptors of human mesangial cells activates transcription factor nuclear factor-kappa B and induces expression and synthesis of monocyte chemoattractant protein-1, IL-8, and IFN-inducible protein 10

J Immunol. 1997 Oct 1;159(7):3474-82.

Abstract

The mechanisms of glomerular damage in IgA nephropathy remain undefined. Mesangial cells (MC) possess Fc receptors for IgA (Fc alpha R), and their occupancy triggers cytokine expression, cell proliferation, and extracellular matrix synthesis. In cultured human MC we examined the effects of soluble IgA aggregates (AIgA) on the activation of nuclear factor-kappa B (NF-kappa B) and the production of proinflammatory chemokines monocyte chemoattractant protein-1 (MCP-1), IL-8, and IFN-inducible protein-10 (IP-10). The exposure of MC to AIgA rapidly activated a NF-kappa B complex constituted of p50 and p65 subunits. NF-kappa B activation was dose dependent, abolished by preincubation with IgA Fc fragments (indicating that AIgA effects occur via specific Fc alpha R), and attenuated by kinase inhibitors. MC stimulation with AIgA increased the mRNA expression of MCP-1, IL-8, and IP-10 in a time- and dose-dependent manner. Maximal expression of IL-8 was observed at 3 h (4.5-fold), while IP-10 and MCP-1 peaked at 6 h (5-fold for both). AIgA also induced biosynthesis and release of the chemokines, which presented biological activity in neutrophil and monocyte chemoattractant assays, peaking at 6 and 9 h, respectively. MC pretreatment with the antioxidant pyrrolidine dithiocarbamate inhibited NF-kappa B activation and chemokine mRNA expression. This study shows that stimulation of Fc alphaR in MC induces gene expression of MCP-1, IL-8, and IP-10, a process partially mediated by NF-kappa B activation. These data may be of importance for a better understanding of the pathogenesis of glomerular damage in IgA immune complex-related diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD / metabolism*
  • Cells, Cultured
  • Chemokine CCL2 / biosynthesis*
  • Chemokine CCL2 / genetics
  • Chemokine CXCL10
  • Chemokines / biosynthesis*
  • Chemokines / genetics
  • Chemokines, CXC*
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / immunology
  • Glomerular Mesangium / cytology
  • Glomerular Mesangium / immunology*
  • Glomerular Mesangium / metabolism
  • Humans
  • Immunoglobulin A / metabolism*
  • Immunoglobulin A / pharmacology
  • Interferon-gamma*
  • Interleukin-8 / biosynthesis*
  • Interleukin-8 / genetics
  • NF-kappa B / metabolism*
  • NF-kappa B / pharmacology
  • Receptors, Fc / metabolism*
  • Solubility
  • Transcription, Genetic / drug effects
  • Transcription, Genetic / immunology
  • Transcriptional Activation / immunology

Substances

  • Antigens, CD
  • Chemokine CCL2
  • Chemokine CXCL10
  • Chemokines
  • Chemokines, CXC
  • Fc(alpha) receptor
  • Immunoglobulin A
  • Interleukin-8
  • NF-kappa B
  • Receptors, Fc
  • Interferon-gamma