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* Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461;
Department of Autoimmunity, Biogen Idec, Cambridge, MA 02142; and
Division of Rheumatology, Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104; and
Irving and Ruth Claremon Research Laboratory, Division of Rheumatology, Albert Einstein College of Medicine, Bronx, NY 10461
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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants R01-AR-48692, the P01-AI-51392 (to C.P.) R01-AR-34156 (to R.A.E.), and R01-AI-063626 (to R.A.E.), a research grant from Biogen Idec (to C.P.), and grants from the Lupus Research Institute, the Arthritis Foundation, the Alliance for Lupus Research, and the Lupus Foundation of South Jersey (to R.A.E.).
2 Address correspondence and reprint requests to Dr. Chaim Putterman, Division of Rheumatology, Forchheimer 701N, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461. E-mail address: putterma{at}aecom.yu.edu
3 Abbreviations used in this paper: TNFRSF, TNF-receptor superfamily; SLE, systemic lupus erythematosus; TWEAK, TNF-like weak inducer of apoptosis; LN, lupus nephritis; cGVH, chronic graft-vs-host disease; WT, wild type; KO, knockout; EAE, experimental allergic encephalomyelitis; MMP, matrix metalloproteinase.
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