Abstract
Introduction
Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a recently identified proinflammatory cytokine of the TNF superfamily that functions through binding to Fn14 receptor in target cells. TWEAK has multiple biological activities. Studies show that TWEAK plays an important role in immune inflammatory diseases. Recent work has revealed that TWEAK may play an important role in the pathogenesis of kidney damage, including in systemic lupus erythematosus (SLE), where its concentration in urine was correlated with the level of activity of lupus nephritis (LN).
Objective
The major focus of this review is to discuss the recent studies on TWEAK and its possible role in the pathogenesis of LN, and the therapeutic potential of modulating this pathway in LN.
Results and conclusion
TWEAK plays a key role in the pathogenesis of LN through activation of multiple down-signaling pathway, inducing proinflammatory cytokines and chemokines, affecting cell proliferation/apoptosis and inducing renal IgG deposition. TWEAK blockade may be a novel therapeutic approach to reducing renal damage in SLE.
Similar content being viewed by others
References
Chicheportiche Y, Bourdon PR, Xu H, et al. TWEAK, a new secreted ligand in the tumor necrosis factor family that weakly induces apoptosis. J Biol Chem. 1997;272(51):32401–10.
Desplat-Jego S, Creidy R, Varriale S, et al. Anti-TWEAK monoclonal antibodies reduce immune cell infiltration in the central nervous system and severity of experimental autoimmune encephalomyelitis. Clin Immunol. 2005;117:15–23.
Zhao Z, Burkly LC, Campbell S, et al. TWEAK/Fn14 interactions are instrumental in the pathogenesis of nephritis in the chronic graft-versus-host model of systemic lupus erythematosus. J Immunol. 2007;179:7949–58.
Campbell S, Michaelson J, Burkly L, et al. The role of TWEAK/Fn14 in the pathogenesis of inflammation and systemic autoimmunity. Front Biosci. 2004;9:2273–84.
Chen T, Guo ZP, Li MM, et al. Tumour necrosis factor-like weak inducer of apoptosis (TWEAK), an important mediator of endothelial inflammation, is associated with the pathogenesis of Henoch-Schonlein purpura. Clin Exp Immunol. 2011;166(1):64–71.
Sanz AB, Sanchez-Nino MD, Izquierdo MC, et al. TWEAK activates the non-canonical NFκB pathway in murine renal tubular cells: modulation of CCL21. PLoS ONE. 2010;5:e8955.
Sanz1 AB, Sánchez Sánchez-Nino1 MaD, et al. The facilitator in acute kidney injury: TWEAK. Nefrología. 2008;6:587–592.
Kamata K, Kamijo S, Nakajima A, et al. Involvement of TNF-like weak inducer of apoptosis in the pathogenesis of collagen-induced arthritis. J Immunol. 2006;177:6433–9.
Zheng TS, Burkly LC. No end in site: TWEAK/Fn14 activation and autoimmunity associated- end-organ pathologies. J Leukoc Biol. 2008;84:338–47.
Wiley SR, Winkles JA. TWEAK, a member of the TNF superfamily, is a multifunctional cytokine that binds the TweakR/Fn14 receptor. Cytokine Growth Factor Rev. 2003;14:241–9.
Winkles JA. The TWEAK-Fn14 cytokine-receptor axis: discovery, biology and therapeutic targeting. Nat Rev Drug Discov. 2008;7:411–4.
Kaplan MJ, Lewis EE, Shelden EA, et al. The apoptotic ligands TRAIL, TWEAK, and Fas ligand mediate monocyte death induced by autologous lupus T cells. J Immunol. 2002;169:6020–9.
Kaptein A, Jansen M, Dilaver G, et al. Studies on the interaction between TWEAK and the death receptor WSL-1/TRAMP (DR3). FEBS Lett. 2000;485:135–41.
Bossen C, Ingold K, Tardivel A, et al. Interactions of tumor necrosis factor (TNF) and TNF receptor family members in the mouse and human. J Biol Chem. 2006;281:13946–71.
Phillips TA, Ni J, Hunt JS. Death-inducing tumour necrosis factor (TNF) superfamily ligands and receptors are transcribed in human placentae, cytotrophoblasts, placental macrophages and placental cell lines. Placenta. 2001;22:663–72.
Marsters SA, Sheridan JP, Pitti RM, Brush J, Goddard A, Ashkenazi A. Identification of a ligand for the death-domain-containing receptor Apo3. Curr Biol. 1998;8:525–8.
Pradet-Balade B, Medema JP, Lopez-Fraga M, et al. An endogenous hybrid mRNA encodes TWE-PRIL, a functional cell surface TWEAK-APRIL fusion protein. EMBO J. 2002;21:5711–20.
Semov A, Semova N, Lacelle C, et al. Alterations in TNF- and IL-related gene expression in space-flown WI-38 human fibroblasts. FASEB J. 2002;16:899–901.
Scholzke MN, Rottinger A, Murikinati S, et al. TWEAK regulates proliferation and differentiation of adult neural progenitor cells. Mol Cell Neurosci. 2011;46(1):325–32.
Munoz-Garcia B, Madrigal-Matute J, Moreno JA, et al. TWEAK-Fn14 interaction enhances plasminogen activator inhibitor 1 and tissue factor expression in atherosclerotic plaques and in cultured vascular smooth muscle cells. Cardiovasc Res. 2011;89(1):225–33.
Feng SY, Guo Y, Factor VM, et al. The Fn14 immediate-early response gene is induced during liver regeneration and highly expressed in both human and murine hepatocellular carcinomas. Am J Pathol. 2000;156:1253–61.
Gao HX, Campbell SR, Burkly LC, et al. TNF-like weak inducer of apoptosis (TWEAK) induces inflammatory and proliferative effects in human kidney cells. Cytokine. 2009;46:24–35.
Campbell S, Burkly LC, Gao HX, Browning B, et al. Proinflammatory effects of TWEAK/Fn14 interactions in glomerular mesangial cells. J Immunol. 2006;176:1889–98.
Wiley SR, Cassiano L, Lofton T, et al. A novel TNF receptor family member binds TWEAK and is implicated in angiogenesis. Immunity. 2001;15:837–46.
Justo P, Sanz AB, Sanchez-Nino MD, Winkles JA, Lorz C, Egido J, Ortiz A. Cytokine cooperation in renal tubular cell injury: the role of TWEAK. Kidney Int. 2006;70:1750–8.
Kessler D, Dethlefsen S, Haase I, et al. Fibroblasts in mechanically stressed collagen lattices assume a “synthetic” phenotype. J Biol Chem. 2001;276:36575–85.
Waldman M, Madaio MP. Pathogenic autoantibodies in lupus nephritis. Lupus. 2005;14:19–24.
Ortiz A, Sanz AB, García BM, et al. Considering TWEAK as a target for therapy in renal and vascular injury. Cytokine Growth Factor. 2009;20:251–8.
Lu J, Kwan BC, Lai FM, et al. Gene expression of TWEAK/Fn14 and IP-10/CXCR3 in glomerulus and tubulointerstitium of patients with lupus nephritis. Nephrology. 2011;16(4):426–32.
Chicheportiche Y, Fossati-Jimack L, Moll S, Ibnou-Zekri N, Izui S. Down-regulated expression of TWEAK mRNA in acute and chronic inflammatory pathologies. Biochem Biophys Res Commun. 2000;279:162–5.
Schwartz N, Rubinstein T, Burkly LC et al. Urinary TWEAK as a biomarker of lupus nephritis: a multicenter cohort study. Arthr Res Ther. 2009;11:143–53.
Gao H-X, Campbell SR, Burkly LC, et al. TNF-like Weak Inducer of Apoptosis (TWEAK) induces potent inflammatory and proliferative effects in human kidney cells. Cytokine. 2009;46:24–35.
Molano A, Lakhani P, Aran A, et al. TWEAK stimulation of kidney resident cells in the pathogenesis of graft versus host induced lupus nephritis. Immunol Lett. 2009;125:119–28.
Bonizzi G, Karin M. The two NFkB activation pathways and their role in innate and adaptive immunity. Trends Immunol. 2004;25:280–8.
Lin CH, Wang SC, Ou TT, et al. IκBα promoter polymorphisms in patients with systemic lupus erythematosus. J Clin Immunol. 2007;28:207–13.
Yamamoto Y, Gaynor RB. Therapeutic potential of inhibition of the NF-kappaB pathway in the treatment of inflammation and cancer. J Clin Invest. 2001;107:135–42.
Neurath MF, Fuss I, Schurmann G, et al. Cytokine gene transcrition by NF-kappa B family members in patients with inflammatory bowel disease. Ann N Y Acad Sci. 1998;859:149–59.
Grimm S, Bauer MK, Baeuerle PA, et al. Bcl-2 down-regulates the activity of transcription factor NF-KB induced upon apoptosis. J Cell Biol. 1996;134:13–23.
Silverman N, Maniatis T. NF-kB signaling pathways in mammalian and insect innate immunity. Genes Dev. 2001;15(18):2321–42.
Li Q, Verma IM. NF-kappaB regulation in the immune system. Nat Rev Immunol. 2002;2(10):725–34.
Locksley RM, Killeen N, Lenardo MJ. The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell. 2001;104(4):487–501.
Zheng L, Sinniah R, Hsu SI. In situ glomerular expression of activated NF-kappaB in human lupus nephritis and other non-proliferative proteinuric glomerulopathy. Virchows Arch. 2006;448(2):172–83.
Burgos P, Metz C, Bull P, et al. Increased expression of c-rel, from the NF-kappaB/Rel family, in T cells from patients with systemic lupus erythematosus. J Rheumatol. 2000;27:116–27.
Khaled AR, Soares LS, Butfiloski EJ, et al. Inhibition of the p50 (NKkappaB1) subunit of NF-kappaB by phosphorothioate-modified antisense oligodeoxynucleotides reduces NF-kappaB expression and immunoglobulin synthesis in murine B cells. Clin Immunol Immunopathol. 1997;83(3):254–63.
Schwaninger M, Inta I, Herrmann O. NF-kappaB signalling in cerebral ischaemia. Biochem Soc Trans. 2006;34(6):1291–4.
Roos C, Wicovsky A, Müller N, et al. Soluble and transmembrane TNF-like weak inducer of apoptosis differentially activate the classical and noncanonical NF-B pathway. J Immunol. 2010;185:1593–605.
Li H, Mittal A, Paul PK, et al. Tumor necrosis factor-related weak inducer of apoptosis augments matrix metalloproteinase 9 (MMP-9) production in skeletal muscle through the activation of nuclear factor inducing kinase and p38 mitogen-activated protein kinase, a potential role of MMP-9 in myopathy. J Biol Chem. 2009;284:4439–50.
Kumar M, Makonchuk DY. TNF-like weak inducer of apoptosis (TWEAK) activates proinflammatory signaling pathways and gene expression through the activation of TGF-beta-activated kinase 1. J Immunol. 2009;182:2439–48.
Harada N, Nakayama M, Nakano H. Pro-inflammatory effect of TWEAK/Fn14 interaction on human umbilical vein endothelial cells. Biochem Biophys Res Commun. 2002;299:488–93.
Donohue PJ, Richards CM. TWEAK is an endothelial cell growth and chemotactic factor that also potentiates FGF-2 and VEGF-A mitogenic activity. Arterioscler Thromb Vasc Biol. 2003;23:594–600.
Saas P, Boucraut J, Walker PR, et al. TWEAK stimulation of astrocytes and the proinflammatory consequences. Glia. 2000;32:102–7.
Kumar M, Makonchuk DY, Li H, et al. TNF-like weak inducer of apoptosis (TWEAK) activates proinflammatory signaling pathways and gene expression through the activation of TGF-beta-activated kinase 1. J Immunol. 2009;15:2439–48.
Nakashima H, Akahoshi M, Masutani K. Th1/Th2 balance of SLE patients with lupus nephritis. Rinsho Byori. 2006;54:706–13.
Bagavant H, Fu SM. Pathogenesis of kidney disease in systemic lupus erythematosus. Curr Opin Rheumatol. 2009;21:489–94.
Kelley VR, Rovin BH. Chemokines: therapeutic targets for autoimmune and inflammatory renal disease. Springer Semin Immunopathol. 2003;24:411–21.
Maule WJ. Pathogenesis and future treatments of systemic lupus erythematosus: the role of cytokines and anti-cytokines? Med Technol SA. 2011;25:5–17.
Perper SJ, Browning B, Burkly LC, et al. TWEAK is a novel arthritogenic mediator. J Immunol. 2006;177:2610–20.
Moore KJ, Wada T, Barbee SD, Kelley VR. Gene transfer of RANTES elicits autoimmune renal injury in MRL-Fas(1pr) mice. Kidney Int. 1998;53:1631–41.
Hasegawa H, Kohno M, Sasaki M, et al. Antagonist of monocyte chemoattractant protein 1 ameliorates the initiation and progression of lupus nephritis and renal vasculitis in MRL/lpr mice. Arthr Rheum. 2003;48:2555–66.
Tesch GH, Maifert S, Schwarting A, Rollins BJ, Kelley VR. Monocyte chemoattractant protein 1-dependent leukocytic infiltrates are responsible for autoimmune disease in MRL-Fas (lpr) mice. J Exp Med. 1999;190:1813–24.
Sugito T, Mineshiba F, Zheng C. Transient TWEAK overexpression leads to a general salivary epithelial cell proliferation. Oral Dis. 2009;15(1):76–81.
Kirim S, Tamer T, Saime P, et al. Apoptosis and proliferating cell nuclear antigen in lupus nephritis (class IV) and membranoproliferative glomerulonephritis. Ren Fail. 2005;27:107–13.
Lynch CN, Wang YC. TWEAK induces angiogenesis and proliferation of endothelial cells. J Biol Chem. 1999;274:8455–9.
Benjamin LE, Keshet E. Conditional switching of vascular endothelial growth factor (VEGF) expression in tumors: induction of endothelial cell shedding and regression of hemangioblastoma-like vessels by VEGF withdrawal. Proc Natl Acad Sci USA. 1997;94:8761–6.
Donohue PJ, Richards CM, Brown SAN. TWEAK is an endothelial cell growth and chemotactic factor that also potentiates FGF-2 and VEGF-A mitogenic activity. Arteriosclerosis Thrombosis Vasc Biol. 2003;23:594–600.
Ferluga D. Vascular pathology in systemic lupus erythematosus: crossroads of immune complex vasculitis and vasculopathy, thrombotic microangiopathy and arteriosclerosis. Relev Topics Immunopathol. 1999;32:481–3.
Nakayama M, Ishidoh K, Kayagaki N, et al. Multiple pathways of TWEAK-induced cell death. J Immunol. 2002;168:734–43.
Mannik M, Merrill CE, Stamps LD, Wener MH. Multiple autoantibodies form the glomerular immune deposits in patients with systemic lupus erythematosus. J Rheumatol. 2003;30:1495–504.
Zhang X, Winkles JA, Gongora MC. TWEAK-Fn14 pathway inhibition protects the integrity of the neurovascular unit during cerebral ischemia. J Cereb Blood Flow Metab. 2007;27:534–44.
Polavarapu R, Gongora MC, Winkles JA, Yepes M. Tumor necrosis factor-like weak inducer of apoptosis increases the permeability of the neurovascular unit through nuclear factor-κB pathway activation. J Neurosci. 2005;25:10094–110.
Author information
Authors and Affiliations
Corresponding author
Additional information
Responsible Editor: Graham Wallace.
Rights and permissions
About this article
Cite this article
Liu, ZC., Zhou, QL. Tumor necrosis factor-like weak inducer of apoptosis and its potential roles in lupus nephritis. Inflamm. Res. 61, 277–284 (2012). https://doi.org/10.1007/s00011-011-0420-8
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00011-011-0420-8