Pathogenic role of NF-kappaB activation in tubulointerstitial inflammatory lesions in human lupus nephritis

J Histochem Cytochem. 2008 May;56(5):517-29. doi: 10.1369/jhc.7A7368.2008. Epub 2008 Feb 18.

Abstract

In vitro and in vivo experimental studies suggest that the transcription factor NF-kappaB plays a role in tubulointerstitial injury. We investigated possible cellular and molecular mechanisms involving NF-kappaB activation in the progression of tubulointerstitial lesions in human lupus nephritis (LN). Paraffin-embedded renal biopsies from 50 patients with LN and six control patients with minimal change disease (MCD) were examined by Southwestern histochemistry for in situ detection of active NF-kappaB and AP-1. Immunohistochemistry was performed to examine the expression of NF-kappaB, AP-1, and NF-kappaB regulatory proteins (IkappaB-alpha, p-IkappaB-alpha, and IKK-alpha proteins), as well as NF-kappaB and AP-1 downstream target proinflammatory molecules (ICAM-1, TNF-alpha, IL-1beta, IL-6, and GM-CSF) and NF-kappaB upstream signaling molecules (CD40 and CD40L). We observed extensive upregulation of activated NF-kappaB in renal tubular cells and interstitial cells, in parallel with overactivation of transcription factor AP-1 in LN, as compared with normal controls and MCD. Tubular expression of activated NF-kappaB correlated well with the degree of tubulointerstitial histopathological indices and/or renal function. Tubulointerstitial IKK-alpha expression was specifically upregulated in LN. IkappaB-alpha and p-IkappaB-alpha were detected only in interstitial cells in LN. Tubulointerstitial expression levels of NF-kappaB and AP-1 downstream inflammatory molecules and NF-kappaB upstream signaling molecules CD40 and CD40L were markedly enhanced in LN as compared with MCD or normal controls and were associated with tubulointerstitial histopathological indices and/or renal function. The results suggest that altered IKK-alpha expression and NF-kappaB activation along with AP-1 overexpression may play a pathogenic role in tubulointerstitial injury in human LN mediated through a network of downstream proinflammatory molecules.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • CD40 Antigens / genetics
  • CD40 Antigens / immunology
  • CD40 Antigens / metabolism
  • CD40 Ligand / genetics
  • CD40 Ligand / immunology
  • CD40 Ligand / metabolism
  • Cytokines / genetics
  • Cytokines / metabolism
  • Female
  • Gene Expression Regulation / immunology
  • Humans
  • I-kappa B Kinase / genetics
  • I-kappa B Kinase / immunology
  • I-kappa B Kinase / metabolism
  • Immunohistochemistry
  • Inflammation / metabolism
  • Inflammation / pathology
  • Intercellular Adhesion Molecule-1 / genetics
  • Intercellular Adhesion Molecule-1 / immunology
  • Intercellular Adhesion Molecule-1 / metabolism
  • Kidney Tubules / immunology
  • Kidney Tubules / metabolism*
  • Lupus Nephritis / metabolism
  • Lupus Nephritis / pathology*
  • Male
  • NF-kappa B / genetics
  • NF-kappa B / immunology
  • NF-kappa B / metabolism*
  • Phosphorylation
  • Signal Transduction / immunology
  • Transcription Factor AP-1 / genetics
  • Transcription Factor AP-1 / immunology
  • Transcription Factor AP-1 / metabolism

Substances

  • CD40 Antigens
  • Cytokines
  • NF-kappa B
  • Transcription Factor AP-1
  • Intercellular Adhesion Molecule-1
  • CD40 Ligand
  • CHUK protein, human
  • I-kappa B Kinase