The role of tumour necrosis factor (TNF-α) signalling adapters in lupus nephritis (LN) is poorly understood. This study investigated renal expression of TNF-α and TNF signalling adapter proteins, including TNF receptor-associated death domain protein (TRADD), receptor-interacting protein (RIP) and TNF receptor-associated factor-2 (TRAF-2) in patients with LN. The renal expression of proliferating cell nuclear antigen (PCNA) and CD68 was also measured. The study showed that glomerular and tubular expression of TNF-α, TRADD, RIP and TRAF-2 was significantly up-regulated in class III and IV LN in which the intense staining was observed on the crescents, proximal and distal tubules and interstitial mononuclear cells. The number of PCNA-positive cells and CD68-positive cells (macrophages) was increased obviously in class III and IV LN. There was a correlation between the expression levels of TNF-α, TRADD, RIP, TRAF-2 and the number of PCNA-positive or CD68-positive cells and active index of renal pathology. These findings suggest that TNF-α and TNF-α adapters in patients with LN play a role in immunopathogenic injury via transmitting abnormal cell proliferating and proinflammatory signals. The findings have provided further insights into the role of TNF-α and its adapter proteins in the pathogenesis of LN and have important therapeutic implications.
7 Vielhauer V Mayadas TN . Functions of TNF and its receptors in renal disease: distinct roles in inflammatory tissue injury and immune regulation. Semin Nephrol2007; 27: 286–308.
8.
8 Aringer M Smolen JS . Cytokine expression in lupus kidneys. Lupus2005; 14: 13–18.
9.
9 Studnicka-Benke A Steiner G Petera P Smolen JS . Tumour necrosis factor alpha and its soluble receptors parallel clinical disease and autoimmune activity in systemic lupus erythematosus. Br J Rheumatol1996; 35: 1067–1074.
10.
10 Takemura T Yoshioka K Murakami K . Cellular localization of inflammatory cytokines in human glomerulonephritis. Virchows Arch1994; 424: 459–464.
11.
11 Herrera-Esparza R Barbosa-Cisneros O Villalobos-Hurtado R Avalos-Diaz E . Renal expression of IL-6 and TNFalpha genes in lupus nephritis. Lupus1998; 7: 154–158.
12.
12 Aringer M Smolen JS . SLE - Complex cytokine effects in a complex autoimmune disease: tumor necrosis factor in systemic lupus erythematosus. Arthritis Res Ther2003; 5: 172–177.
13.
13 Flanc RS Roberts MA Strippoli GF Chadban SJ Kerr PG Atkins RC . Treatment for lupus nephritis. Cochrane Database Syst Rev2004; XXX: CD002922.
14.
14 Aringer M Smolen JS . Tumour necrosis factor and other proinflammatory cytokines in systemic lupus erythematosus: a rationale for therapeutic intervention. Lupus2004; 13: 344–347.
15.
15 Kollias G Kontoyiannis D . Role of TNF/TNFR in autoimmunity: specific TNF receptor blockade may be advantageous to anti-TNF treatments. Cytokine Growth Factor Rev2002; 13: 315–321.
16.
16 Locksley RM Killeen N Lenardo MJ . The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell2001; 104: 487–501.
17.
17 Ting AT Pimentel-Muiños FX Seed B . RIP mediates tumor necrosis factor receptor 1 activation of NF-κB but not Fas/APO-1-initiated apoptosis. EMBO J1996; 15: 6189–6196.
18.
18 Zhu L Yang X Chen W . Decreased expressions of the TNF-alpha signaling adapters in peripheral blood mononuclear cells (PBMCs) are correlated with disease activity in patients with systemic lupus erythematosus. Clin Rheumatol2007; 26: 1481–1489.
19.
19 Li ZR Hromchak R Mudipalli A Bloch A . Tumor suppressor proteins as regulators of cell differentiation. Cancer Res1998; 58: 4282–4287.
20.
20 Shin DM Voravud N Ro JY Lee JS Hong WK Hittelman WN . Sequential increases in proliferating cell nuclear antigen expression in head and neck tumorigenesis: a potential biomarker. J Natl Cancer Inst1993; 85: 971–978.
21.
21 Iyengar B . Expression of proliferating cell nuclear antigen (PCNA): proliferative phase functions and malignant transformation of melanocytes. Melanoma Res1994; 4: 293–295.
22.
22 Petri M . Review of classification criteria for systemic lupus erythematosus. Rheum Dis Clin North Am2005; 31: 245–254 vi.
23.
23 Font J Cervera R . 1982 revised criteria for classification of systemic lupus erythematosus–ten years later. Lupus1993; 2: 339–341 discussion 343.
24.
24 Tan EM Cohen AS Fries JF . The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum1982; 25: 1271–1277.
25.
25 Bombardier C Gladman DD Urowitz MB Caron D Chang CH . Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE. Arthritis Rheum1992; 35: 630–640.
26.
26 Weening JJ D'Agati VD Schwartz MM . The classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol2004; 15: 241–250.
27.
27 Weening JJ D'Agati VD Schwartz MM . The classification of glomerulonephritis in systemic lupus erythematosus revisited. Kidney Int2004; 65: 521–530.
28.
28 Pirani C . L. S-M, Koss, M. Evaluation of renal biopsy. In: Sommers, C, (ed), Pathology Decennial , (1965–1975). 1st ed.New York: Appleton Century Crofts; 1975, 109–163.
29.
29 Austin HA Muenz LR Joyce KM Antonovych TT Balow JE . Diffuse proliferative lupus nephritis: identification of specific pathologic features affecting renal outcome. Kidney Int1984; 25: 689–695.
30.
30 Baud V Karin M . Signal transduction by tumor necrosis factor and its relatives. Trends Cell Biol2001; 11: 372–377.
31.
31 Wu AJ Hua H Munson SH McDevitt HO . Tumor necrosis factor-alpha regulation of CD4+CD25+ T cell levels in NOD mice. Proc Natl Acad Sci U S A2002; 99: 12287–12292.
32.
32 Malide D Russo P Bendayan M . Presence of tumor necrosis factor alpha and interleukin-6 in renal mesangial cells of lupus nephritis patients. Hum Pathol1995; 26: 558–564.
33.
33 Hsu H Xiong J Goeddel DV . The TNF receptor 1-associated protein TRADD signals cell death and NF-kappa B activation. Cell1995; 81: 495–504.
34.
34 Hsu H Shu HB Pan MG Goeddel DV . TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1 signal transduction pathways. Cell1996; 84: 299–308.
35.
35 Hsu H Huang J Shu HB Baichwal V Goeddel DV . TNF-dependent recruitment of the protein kinase RIP to the TNF receptor-1 signaling complex. Immunity1996; 4: 387–396.
36.
36 Chinnaiyan AM O'Rourke K Tewari M Dixit VM . FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis. Cell1995; 81: 505–512.
37.
37 Liu ZG Hsu H Goeddel DV Karin M . Dissection of TNF receptor 1 effector functions: JNK activation is not linked to apoptosis while NF-kappaB activation prevents cell death. Cell1996; 87: 565–576.
38.
38 Zhang J Cado D Chen A Kabra NH Winoto A . Fas-mediated apoptosis and activation-induced T-cell proliferation are defective in mice lacking FADD/Mort1. Nature1998; 392: 296–300.
39.
39 Darnay BG Aggarwal BB . Early events in TNF signaling: a story of associations and dissociations. J Leukoc Biol1997; 61: 559–566.
40.
40 Rothe M Pan MG Henzel WJ Ayres TM Goeddel DV . The TNFR2-TRAF signaling complex contains two novel proteins related to baculoviral inhibitor of apoptosis proteins. Cell1995; 83: 1243–1252.
41.
41 Yu CC Filipe MI . Update on proliferation-associated antibodies applicable to formalin-fixed paraffin-embedded tissue and their clinical applications. Histochem J1993; 25: 843–853.
42.
42 Waseem NH Lane DP . Monoclonal antibody analysis of the proliferating cell nuclear antigen (PCNA). Structural conservation and the detection of a nucleolar form. J Cell Sci1990; 96: 121–129.
43.
43 Dreinhofer KE Akerman M Willen H Anderson C Gustafson P Rydholm A . Proliferating cell nuclear antigen (PCNA) in high-grade malignant fibrous histiocytoma: prognostic value in 48 patients. Int J Cancer1994; 59: 379–382.
44.
44 Nath KA . Tubulointerstitial changes as a major determinant in the progression of renal damage. Am J Kidney Dis1992; 20: 1–17.
