title: Pathogenic role of NF-kappaB activation in tubulointerstitial inflammatory lesions in human lupus nephritis.
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.
authors.affiliation: Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Ling
authors.initials: L
authors.lastname: Zheng
authors.forename: Raja
authors.initials: R
authors.lastname: Sinniah
authors.forename: Stephen I-Hong
authors.initials: SI
authors.lastname: Hsu
mesh_terms: D000328:Adult; D019013:CD40 Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D023201:CD40 Ligand / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007684:Kidney Tubules / Q000276:immunology / Q000378:metabolism*; D008181:Lupus Nephritis / Q000378:metabolism / Q000473:pathology*; D008297:Male; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction / Q000276:immunology; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D019013:CD40 Antigens; D016207:Cytokines; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D018799:Intercellular Adhesion Molecule-1; D023201:CD40 Ligand; C496559:CHUK protein, human; D051550:I-kappa B Kinase