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

Ling Zheng ¹, Raja Sinniah ¹ and Stephen I-Hong Hsu ^1*

¹ 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)

^* To whom correspondence should be addressed. E-mail: Stephen.Hsu{at}medicine.ufl.edu.

Submitted on October 22, 2007
Accepted on 6 February 2008

	Abstract

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 6 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, 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-1, 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 to normal controls and MCD. Tubular expression of activated NF-B correlated well with the degree of tubulointerstitial histopathologic indices and/or renal function. Tubulointerstitial IKK- expression was specifically upregulated in LN. IB- and p-IB- were only detected 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 to MCD or normal controls, and were associated with tubulointerstitial histopathologic 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.

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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