Pathogenic Role of NF-κB Activation in Tubulointerstitial Inflammatory Lesions in Human Lupus Nephritis

Abstract

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