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

In vitro and in vivo experimental studies suggest that the transcription factor NF-kappa B plays a role in tubulointerstitial injury. We investigated possible cellular and molecular mechanisms involving NF-kappa B 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-kappa B and AP-1. Immunohistochemistry was performed to examine the expression of NF-kappa B, AP-1, and NF-kappa B regulatory proteins (IKB-alpha, p-I kappa B-alpha, and IKK-alpha proteins), as well as NF-kappa B and AP-1 downstream target proinflammatory molecules (ICAM-1, TNF-alpha, IL-1 beta, IL-6, and GM-CSF) and NF-kappa B upstream signaling molecules (CD40 and CD40L). We observed extensive upregulation of activated NF-kappa B 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-kappa B correlated well with the degree of tubulointerstitial histopathological indices and/or renal function. Tubulointerstitial IKK-alpha expression was specifically upregulated in LN. I kappa B-alpha and p-I kappa B-alpha were detected only in interstitial cells in LN. Tubulointerstitial expression levels of NF-kappa B and AP-1 downstream inflammatory molecules and NF-kappa B 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-kappa B 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.