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

Ling Zheng, Raja Sinniah and Stephen I-Hong Hsu

Departments of Pathology (LZ,RS) and Medicine (SI-HH), Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Renal Division and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts (SI-HH); and Department of Anatomic Pathology, Royal Perth Hospital and University of Western Australia, Perth, Australia (RS)

Correspondence to: Stephen I-Hong Hsu, Division of Nephrology, Hypertension and Renal Transplantation, College of Medicine, University of Florida, 1600 SW Archer Road, Room NG-4A, PO Box 100224, Gainesville, FL 32610-0224. E-mail: Stephen.Hsu{at}medicine.ufl.edu

In vitro and in vivo experimental studies suggest that the transcription factor NF-B plays a role in tubulointerstitial injury. We investigated possible cellular and molecular mechanisms involving NF-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-B and AP-1. Immunohistochemistry was performed to examine the expression of NF-B, AP-1, and NF-B regulatory proteins (IB-, p-IB-, and IKK- proteins), as well as NF-B and AP-1 downstream target proinflammatory molecules (ICAM-1, TNF-, IL-1β, IL-6, and GM-CSF) and NF-B upstream signaling molecules (CD40 and CD40L). We observed extensive upregulation of activated NF-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-B correlated well with the degree of tubulointerstitial histopathological indices and/or renal function. Tubulointerstitial IKK- expression was specifically upregulated in LN. IB- and p-IB- were detected only in interstitial cells in LN. Tubulointerstitial expression levels of NF-B and AP-1 downstream inflammatory molecules and NF-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- expression and NF-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. (J Histochem Cytochem 56:517–529, 2008)

Key Words: nuclear factor-B • AP-1 • inhibitor B- • inhibitor IB kinase- • lupus nephritis • tubulointerstitial lesion • proinflammatory molecules • adhesion molecules • CD40/CD40L

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