title: Polymeric IgA increases the synthesis of macrophage migration inhibitory factor by human mesangial cells in IgA nephropathy.
abstract: BACKGROUND
  It has been suggested that polymeric IgA (pIgA) or IgA immune complexes play a significant pathogenic role in IgA nephropathy (IgAN). Macrophage migration inhibitory factor (MIF) shares many activities with other pro-inflammatory cytokines. In human glomerulonephritis, including IgAN, glomerular expression of MIF is found to correlate with progressive renal injury. We hypothesized that deposition of pIgA within the kidney may lead to enhanced synthesis of MIF by mesangial cells.
  
  
  METHODS
  In this study we examined the effect of pIgA and monomeric IgA (mIgA) from randomly selected patients with IgAN in clinical quiescence on the gene expression and protein synthesis of MIF in cultured human mesangial cells (HMC).
  
  
  RESULTS
  Both pIgA and mIgA from IgAN patients or matched healthy controls increased MIF gene expression and protein synthesis in a dose-dependent fashion. The magnitude of MIF protein induction by pIgA (100 microg/ml) was similar to that of tumour necrosis factor-alpha (TNF-alpha) at 10 pg/ml. In all subjects, the induction of MIF was higher for pIgA when compared with mIgA (P < 0.01). Furthermore, the up-regulation of MIF synthesis by either pIgA or mIgA was significantly higher in IgAN patients than in healthy controls (P < 0.05). Similarly, pIgA and mIgA were able to induce TNF-alpha gene expression and protein synthesis in mesangial cells. Incubation of mesangial cells with neutralizing antibody to TNF-alpha reduced the MIF synthesis induced by pIgA.
  
  
  CONCLUSIONS
  We demonstrate that pIgA is capable of inducing MIF and TNF-alpha production in HMC, which may play a major pathogenic role in IgAN. Induction of MIF can be partially blocked by neutralizing antibody to TNF-alpha, suggesting the possibility that up-regulation of MIF synthesis in HMC is mediated via an amplifying proinflammatory loop involving TNF-alpha.
authors.affiliation: Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong.
authors.forename: Joseph C K
authors.initials: JC
authors.lastname: Leung
authors.forename: Sydney C W
authors.initials: SC
authors.lastname: Tang
authors.forename: Loretta Y Y
authors.initials: LY
authors.lastname: Chan
authors.forename: Anita W L
authors.initials: AW
authors.lastname: Tsang
authors.forename: Hui Yao
authors.initials: HY
authors.lastname: Lan
authors.forename: Kar Neng
authors.initials: KN
authors.lastname: Lai
mesh_terms: D000328:Adult; D001483:Base Sequence; D017931:DNA Primers; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology*; D005920:Glomerular Mesangium / Q000098:blood supply / Q000276:immunology* / Q000473:pathology; D005922:Glomerulonephritis, IGA / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D006801:Humans; D007070:Immunoglobulin A / Q000097:blood / Q000627:therapeutic use*; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics*; D008297:Male; D011507:Proteinuria / Q000209:etiology; D011994:Recombinant Proteins / Q000627:therapeutic use; D012016:Reference Values; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000627:therapeutic use
chemical_list: D017931:DNA Primers; D007070:Immunoglobulin A; D008263:Macrophage Migration-Inhibitory Factors; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C034639:polymeric IgA