Presentation: A Potential Role For TNF-Like Weak Inducer of Apoptosis (TWEAK) in the Pathogenesis of Lupus Nephritis (2007)

130 A Potential Role For TNF-Like Weak Inducer of Apoptosis (TWEAK) in the Pathogenesis of Lupus Nephritis

Background: Binding of TWEAK, a novel member of the TNF-ligand superfamily, to the receptor Fn14 stimulates fibroblasts, synoviocytes, and murine mesangial cells (MC) to secrete proinflammatory cytokines and chemokines. Some of these TWEAK-induced chemokines are instrumental in lupus nephritis (LN). In addition, we found that TWEAK inhibition improves LN in the chronic graft versus host model of murine lupus. Furthermore, initial studies indicated that lupus patients display high urine levels of TWEAK that reflect LN disease acitivity.
Purpose: To determine a possible role for TWEAK in the pathogenesis of human lupus nephritis via up-regulation of proinflammatory chemokines and proliferation of human kidney cells.
Methods: Immortalized human MC, podocyte and tubular cell lines (HK2) were used in these studies. Primary cells were used for confirmatory studies when available. Fn14 expression was determined by flow cytometry. The effects of TWEAK stimulation on cytokines and chemokines were detected by real time PCR, multiplex bead and ELISA-based assays. Cell signaling pathways important in TWEAK signaling were investigated by Western blotting for phosphorylated NF-kappaB, IKB, and assay of chemokine secretion induced by TWEAK in cells treated with specific inhibitors. The chemotactic activity of TWEAK-induced chemokines was tested in an in vitro chemotaxis assay using human PBMC.
Results: We studied the effects of TWEAK in human kidney cells including mesangial cells (MC), podocytes and tubular cells, following our demonstration of the presence of the TWEAK receptor Fn14 on these cells. TWEAK induces kidney cells to produce multiple inflammatory mediators, including RANTES, MCP-1, IP-10, MIP-1a, GM-CSF, ICAM-1, and VCAM-1 (2 to 120 fold). Cytokine production is primarily mediated through NF-kB activation, and could be inhibited by soluble Fn14 or novel anti-TWEAK mAb. Supernatants from TWEAK-stimulated MC induced PBMC migration (2 fold), especially monocyte/macrophages, which may then infiltrate into lupus kidneys in vivo. Using blocking antibodies, we determined that the major chemokines responsible for this chemotactic effect were MCP-1 and RANTES. Furthermore, we found that TWEAK significantly promotes the proliferation of human MC.
Conclusion: TWEAK may play a pathogenic role in the development of LN by enhancing renal inflammation and MC proliferation. Blocking TWEAK/Fn14 interactions may be a promising therapeutic target in LN and perhaps other immune-mediated renal diseases.

 H. Gao, None.