Glomerular Expression of Fas Ligand and Bax mRNA in Lupus Nephritis

Badillo-almaráz, IsaÍAs; Daza, Leonel; Avalos‐Díaz, Esperanza; Herrera‐Esparza, Rafael

doi:10.3109/08916930109014697

Cited by 20 publications

(15 citation statements)

References 28 publications

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“…We found that in mesangial cells, similar to what is observed in some tumor cell lines, TWEAK can synergize with IFN-␥ to induce a measurable and significant increase in apoptosis. It is interesting that glomerular cell apoptosis has been linked to the pathogenesis and progression of lupus nephritis (44,45), despite the proliferative phenotype observed in lupus renal disease. Nevertheless, the possibility that in certain cellular microenvironments TWEAK will demonstrate a proliferative effect on mesangial cells has not yet been completely excluded.…”

Section: Discussionmentioning

confidence: 99%

Proinflammatory Effects of Tweak/Fn14 Interactions in Glomerular Mesangial Cells

Campbell

Burkly

Gao

et al. 2006

The Journal of Immunology

150

187

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TNF-like weak inducer of apoptosis, or TWEAK, is a relatively new member of the TNF-ligand superfamily. Ligation of the TWEAK receptor Fn14 by TWEAK has proinflammatory effects on fibroblasts, synoviocytes, and endothelial cells. Several of the TWEAK-inducible cytokines are important in the pathogenesis of kidney diseases; however, whether TWEAK can induce a proinflammatory effect on kidney cells is not known. We found that murine mesangial cells express cell surface TWEAK receptor. TWEAK stimulation of mesangial cells led to a dose-dependent increase in CCL2/MCP-1, CCL5/RANTES, CXCL10/IFN-γ-induced protein 10 kDa, and CXCL1/KC. The induced levels of chemokines were comparable to those found following mesangial cell exposure to potent proinflammatory stimuli such as TNF-α + IL-1β. CXCL11/interferon-inducible T cell α chemoattractant, CXCR5, mucosal addressin cell adhesion molecule-1, and VCAM-1 were up-regulated by TWEAK as well. TWEAK stimulation of mesangial cells resulted in an increase in phosphorylated Iκ-B, while pretreatment with an Iκ-B phosphorylation inhibitor significantly blocked chemokine induction, implicating activation of the NF-κB signaling pathway in TWEAK-induced chemokine secretion. Importantly, the Fn14-mediated proinflammatory effects of TWEAK on kidney cells were confirmed using mesangial cells derived from Fn14-deficient mice and by injection in vivo of TWEAK into wild-type vs Fn14-deficient mice. Finally, TWEAK-induced chemokine secretion was prevented by treatment with novel murine anti-TWEAK Abs. We conclude that TWEAK induces mesangial cells to secrete proinflammatory chemokines, suggesting a prominent role for TWEAK in the pathogenesis of renal injury. Our results support Ab inhibition of TWEAK as a potential new approach for the treatment of chemokine-dependent inflammatory kidney diseases.

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Section: Discussionmentioning

confidence: 99%

Proinflammatory Effects of Tweak/Fn14 Interactions in Glomerular Mesangial Cells

Campbell

Burkly

Gao

et al. 2006

The Journal of Immunology

150

187

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“…As both kidney cell proliferation and apoptosis have been described in LN (27)(28)(29), we assessed renal cell proliferation and apoptosis by Ki-67 and caspase 3 staining, respectively. Renal cell proliferation (seen in both glomerular and tubular compartments) increased significantly in bm12 injected B6 and B6KO mice ( p ϭ 0.0001 for each comparison to the respective control group).…”

Section: Fn14-deficient Mice Have Reduced Renal Igg Deposition Cytokmentioning

confidence: 99%

TWEAK/Fn14 Interactions Are Instrumental in the Pathogenesis of Nephritis in the Chronic Graft-versus-Host Model of Systemic Lupus erythematosus

Zhao

Burkly

Campbell

et al. 2007

The Journal of Immunology

141

143

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TNF-like weak inducer of apoptosis (TWEAK), a member of the TNF superfamily, is a prominent inducer of proinflammatory cytokines in vitro and in vivo. We previously found that kidney cells display the TWEAK receptor Fn14, and that TWEAK stimulation of mesangial cells and podocytes induces a potent proinflammatory response. Several of the cytokines up-regulated in the kidney in response to TWEAK are instrumental in Lupus nephritis; we therefore hypothesized that TWEAK/Fn14 interactions may be important in the cascade(s) leading to renal damage in systemic Lupus erythematosus. In this study, we analyzed the effects of Fn14 deficiency in the chronic graft-vs-host model of SLE, and the benefits of treatment with an anti-TWEAK mAb in this mouse model. We found that anti-nuclear Ab titers were no different between C57BL/6 Fn14 wild-type and deficient mice injected with alloreactive bm12 splenocytes. However, kidney disease was significantly less severe in Fn14 knockout mice. Furthermore, kidney IgG deposition, IL-6, MCP-1, RANTES, and IP-10, as well as macrophage infiltration, were significantly decreased in Fn14-deficient mice with induced lupus. Similarly, mice with induced Lupus treated with an anti-TWEAK neutralizing mAb had significantly diminished kidney expression of IL-6, MCP-1, IL-10, as well as proteinuria, but similar autoantibody titers, as compared with control-treated mice. We conclude that TWEAK is an important mediator of kidney damage that acts by promoting local inflammatory events, but without impacting adaptive immunity in this experimental LN model. Thus, TWEAK blockade may be a novel therapeutic approach to reduce renal damage in SLE.

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“…A fluorescence in situ hybridization study indicated FasL mRNA was expressed in glomeruli in lupus nephritis. 7 However, the role of FasL in glomerular inflammation still remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Mesangial cell Fas ligand: upregulation in human lupus nephritis and NF-?B-mediated expression in cultured human mesangial cells

et al. 2004

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Glomerular Expression of Fas Ligand and Bax mRNA in Lupus Nephritis

Cited by 20 publications

References 28 publications

Proinflammatory Effects of Tweak/Fn14 Interactions in Glomerular Mesangial Cells

Proinflammatory Effects of Tweak/Fn14 Interactions in Glomerular Mesangial Cells

TWEAK/Fn14 Interactions Are Instrumental in the Pathogenesis of Nephritis in the Chronic Graft-versus-Host Model of Systemic Lupus erythematosus

Mesangial cell Fas ligand: upregulation in human lupus nephritis and NF-?B-mediated expression in cultured human mesangial cells

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