TWEAK and the Kidney: the Dual Role of a Multifunctional Cytokine

  • Ana Ortiz
  • M.D. Sanchez-Niño
  • M.C. Izquierdo
  • L.M. Blanco-Colio
  • R. Selgas
  • M. Ruiz-Ortega
  • J. Egido
  • Ana B. Sanz
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 691)


Acute kidney injury (AKI) is a syndrome characterized by an acute loss of renal function. The incidence of AKI is 208 per million population in Europe. There is no established therapy to accelerate the recovery and attempts at preventing AKI are not universally effective. The treatment of most forms of AKI is symptomatic and consists in substitution of renal function by dialysis if renal failure is severe. Despite the reversibility of the loss of renal function in most patients that survive, the mortality of AKI remains high (over 50%) [41].The tubular epithelium is a key cell in the renal injury. Indeed, tubular cell death plays an important role in the AKI and is the main histological correlation with the degree of renal failure [37, 51]. The tubular epithelium also contributes to renal failure by secreting pro-inflammatory cytokines and by the epithelium–mesenchymal differentiation originating fibroblasts and promoting tubular atrophy and interstitial fibrosis [40, 54]. These events are important contributors to progression of chronic kidney disease.


Chronic Kidney Disease Acute Kidney Injury Lupus Nephritis Mesangial Cell Tubular Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Grant support: FIS CP04/00060, 06/0046, SAF03/884, SAF2005-03378, SAF2007/60896, Sociedad Española de Nefrologia, ISCIII-RETIC REDinREN/RD06/0016, Comunidad de Madrid/FRACM/S-BIO0283/2006, and SAF 2007-60896. Salary support: FIS to MCI and AS, MEC to MDSN, and Programa Intensificación Actividad Investigadora (ISCIII/Agencia Laín-Entralgo/CM) to AO.


  1. 1.
    Alderson MR, Armitage RJ, Maraskovsky E, Tough TW, Roux E, Schooley K, Ramsdell F, Lynch DH (1993) Fas transduces activation signals in normal human T lymphocytes. J Exp Med 178:2231–2235CrossRefPubMedGoogle Scholar
  2. 2.
    Ando T, Ichikawa J, Wako M, Hatsushika K, Watanabe Y, Sakuma M, Tasaka K, Ogawa H, Hamada Y, Yagita H, Nakao A (2006) TWEAK/Fn14 interaction regulates RANTES production, BMP-2-induced differentiation, and RANKL expression in mouse osteoblastic MC3T3-E1 cells. Arthritis Res Ther 8:R146CrossRefPubMedGoogle Scholar
  3. 3.
    Burkly LC, Michaelson JS, Hahm K, Jakubowski A, Zheng TS (2007) TWEAKing tissue remodeling by a multifunctional cytokine: role of TWEAK/Fn14 pathway in health and disease. Cytokine 40:1–16CrossRefPubMedGoogle Scholar
  4. 4.
    Campbell S, Burkly LC, Gao HX, Berman JW, Su L, Browning B, Zheng T, Schiffer L, Michaelson JS, Putterman C (2006) Proinflammatory effects of TWEAK/Fn14 interactions in glomerular mesangial cells. J Immunol 176:1889–1898PubMedGoogle Scholar
  5. 5.
    Chicheportiche Y, Bourdon PR, Xu H, Hsu YM, Scott H, Hession C, Garcia I, Browning JL (1997) TWEAK, a new secreted ligand in the tumor necrosis factor family that weakly induces apoptosis. J Biol Chem 272:32401–32410CrossRefPubMedGoogle Scholar
  6. 6.
    de Haij S, Woltman AM, Bakker AC, Daha MR, van KC (2002) Production of inflammatory mediators by renal epithelial cells is insensitive to glucocorticoids. Br J Pharmacol 137:197–204CrossRefPubMedGoogle Scholar
  7. 7.
    Desplat-Jego S, Creidy R, Varriale S, Allaire N, Luo Y, Bernard D, Hahm K, Burkly L, Boucraut J (2005) Anti-TWEAK monoclonal antibodies reduce immune cell infiltration in the central nervous system and severity of experimental autoimmune encephalomyelitis. Clin Immunol 117:15–23CrossRefPubMedGoogle Scholar
  8. 8.
    Desplat-Jego S, Varriale S, Creidy R, Terra R, Bernard D, Khrestchatisky M, Izui S, Chicheportiche Y, Boucraut J (2002) TWEAK is expressed by glial cells, induces astrocyte proliferation and increases EAE severity. J Neuroimmunol 133:116–123CrossRefPubMedGoogle Scholar
  9. 9.
    Donohue PJ, Richards CM, Brown SA, Hanscom HN, Buschman J, Thangada S, Hla T, Williams MS, Winkles JA (2003) TWEAK is an endothelial cell growth and chemotactic factor that also potentiates FGF-2 and VEGF-A mitogenic activity. Arterioscler Thromb Vasc Biol 23:594–600CrossRefPubMedGoogle Scholar
  10. 10.
    Feng SL, Guo Y, Factor VM, Thorgeirsson SS, Bell DW, Testa JR, Peifley KA, Winkles JA (2000) The Fn14 immediate-early response gene is induced during liver regeneration and highly expressed in both human and murine hepatocellular carcinomas. Am J Pathol 156:1253–1261PubMedGoogle Scholar
  11. 11.
    Flyvbjerg A, Bennett WF, Rasch R, van Neck JW, Groffen CA, Kopchick JJ, Scarlett JA (1999) Compensatory renal growth in uninephrectomized adult mice is growth hormone dependent. Kidney Int 56:2048–2054CrossRefPubMedGoogle Scholar
  12. 12.
    Gao HX, Campbell SR, Burkly LC, Jakubowski A, Jarchum I, Banas B, Saleem MA, Mathieson PW, Berman JW, Michaelson JS, Putterman C (2009) TNF-like weak inducer of apoptosis (TWEAK) induces inflammatory and proliferative effects in human kidney cells. Cytokine 46:24–35CrossRefPubMedGoogle Scholar
  13. 13.
    Girgenrath M, Weng S, Kostek CA, Browning B, Wang M, Brown SA, Winkles JA, Michaelson JS, Allaire N, Schneider P, Scott ML, Hsu YM, Yagita H, Flavell RA, Miller JB, Burkly LC, Zheng TS (2006) TWEAK, via its receptor Fn14, is a novel regulator of mesenchymal progenitor cells and skeletal muscle regeneration. EMBO J 25:5826–5839CrossRefPubMedGoogle Scholar
  14. 14.
    Goes N, Urmson J, Vincent D, Halloran PF (1995) Acute renal injury in the interferon-gamma gene knockout mouse: effect on cytokine gene expression. Transplantation 60:1560–1564CrossRefPubMedGoogle Scholar
  15. 15.
    Higashitsuji H, Arii S, Furutani M, Mise M, Monden K, Fujita S, Ishiguro S, Kitao T, Nakamura T, Nakayama H (1995) Expression of cytokine genes during liver regeneration after partial hepatectomy in rats. J Surg Res 58:267–274CrossRefPubMedGoogle Scholar
  16. 16.
    Jakubowski A, Ambrose C, Parr M, Lincecum JM, Wang MZ, Zheng TS, Browning B, Michaelson JS, Baetscher M, Wang B, Bissell DM, Burkly LC (2005) TWEAK induces liver progenitor cell proliferation. J Clin Invest 115:2330–2340CrossRefPubMedGoogle Scholar
  17. 17.
    Justo P, Sanz A, Lorz C, Gomez-Garre D, Mezzano S, Egido J, Ortiz A (2003) Expression of Smac/Diablo in tubular epithelial cells and during acute renal failure. Kidney Int Suppl. S52–S56Google Scholar
  18. 18.
    Justo P, Sanz AB, Sanchez-Nino MD, Winkles JA, Lorz C, Egido J, Ortiz A (2006) Cytokine cooperation in renal tubular cell injury: the role of TWEAK. Kidney Int 70:1750–1758CrossRefPubMedGoogle Scholar
  19. 19.
    Kamata K, Kamijo S, Nakajima A, Koyanagi A, Kurosawa H, Yagita H, Okumura K (2006) Involvement of TNF-like weak inducer of apoptosis in the pathogenesis of collagen-induced arthritis. J Immunol 177:6433–6439PubMedGoogle Scholar
  20. 20.
    Kaplan MJ, Lewis EE, Shelden EA, Somers E, Pavlic R, McCune WJ, Richardson BC (2002) The apoptotic ligands TRAIL, TWEAK, and Fas ligand mediate monocyte death induced by autologous lupus T cells. J Immunol 169:6020–6029PubMedGoogle Scholar
  21. 21.
    Kim SH, Kang YJ, Kim WJ, Woo DK, Lee Y, Kim DI, Park YB, Kwon BS, Park JE, Lee WH (2004) TWEAK can induce pro-inflammatory cytokines and matrix metalloproteinase-9 in macrophages. Circ J 68:396–399CrossRefPubMedGoogle Scholar
  22. 22.
    Locksley RM, Killeen N, Lenardo MJ (2001) The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell 104:487–501CrossRefPubMedGoogle Scholar
  23. 23.
    Lorz C, Benito-Martin A, Boucherot A, Ucero AC, Rastaldi MP, Henger A, Armelloni S, Santamaria B, Berthier CC, Kretzler M, Egido J, Ortiz A (2008) The death ligand TRAIL in diabetic nephropathy. J Am Soc Nephrol 19:904–914CrossRefPubMedGoogle Scholar
  24. 24.
    Lynch CN, Wang YC, Lund JK, Chen YW, Leal JA, Wiley SR (1999) TWEAK induces angiogenesis and proliferation of endothelial cells. J Biol Chem 274:8455–8459CrossRefPubMedGoogle Scholar
  25. 25.
    Maecker H, Varfolomeev E, Kischkel F, Lawrence D, LeBlanc H, Lee W, Hurst S, Danilenko D, Li J, Filvaroff E, Yang B, Daniel D, Ashkenazi A (2005) TWEAK attenuates the transition from innate to adaptive immunity. Cell 123:931–944CrossRefPubMedGoogle Scholar
  26. 26.
    Marsters SA, Sheridan JP, Pitti RM, Brush J, Goddard A, Ashkenazi A (1998) Identification of a ligand for the death-domain-containing receptor Apo3. Curr Biol 8:525–528CrossRefPubMedGoogle Scholar
  27. 27.
    Meighan-Mantha RL, Hsu DK, Guo Y, Brown SA, Feng SL, Peifley KA, Alberts GF, Copeland NG, Gilbert DJ, Jenkins NA, Richards CM, Winkles JA (1999) The mitogen-inducible Fn14 gene encodes a type I transmembrane protein that modulates fibroblast adhesion and migration. J Biol Chem 274:33166–33176CrossRefPubMedGoogle Scholar
  28. 28.
    Metz-Kurschel U, Kurschel E, Wagner K, Aulbert E, Graben N, Philipp T (1990) Folate nephropathy occurring during cytotoxic chemotherapy with high-dose folinic acid and 5-fluorouracil. Ren Fail 12:93–97CrossRefPubMedGoogle Scholar
  29. 29.
    Mitsiades CS, Poulaki V, Fanourakis G, Sozopoulos E, McMillin D, Wen Z, Voutsinas G, Tseleni-Balafouta S, Mitsiades N (2006) Fas signaling in thyroid carcinomas is diverted from apoptosis to proliferation. Clin Cancer Res 12:3705–3712CrossRefPubMedGoogle Scholar
  30. 30.
    Molano A, Lakhani P, Aran A, Burkly LC, Michaelson JS, Putterman C (2009) TWEAK stimulation of kidney resident cells in the pathogenesis of graft versus host induced lupus nephritis. Immunol Lett 125:119–128CrossRefPubMedGoogle Scholar
  31. 31.
    Mueller AM, Pedre X, Kleiter I, Hornberg M, Steinbrecher A, Giegerich G (2005) Targeting fibroblast growth factor-inducible-14 signaling protects from chronic relapsing experimental autoimmune encephalomyelitis. J Neuroimmunol 159:55–65CrossRefPubMedGoogle Scholar
  32. 32.
    Nakayama M, Harada N, Okumura K, Yagita H (2003a) Characterization of murine TWEAK and its receptor (Fn14) by monoclonal antibodies. Biochem Biophys Res Commun 306:819–825CrossRefPubMedGoogle Scholar
  33. 33.
    Nakayama M, Ishidoh K, Kayagaki N, Kojima Y, Yamaguchi N, Nakano H, Kominami E, Okumura K, Yagita H (2002) Multiple pathways of TWEAK-induced cell death. J Immunol 168:734–743PubMedGoogle Scholar
  34. 34.
    Nakayama M, Ishidoh K, Kojima Y, Harada N, Kominami E, Okumura K, Yagita H (2003b) Fibroblast growth factor-inducible 14 mediates multiple pathways of TWEAK-induced cell death. J Immunol 170:341–348PubMedGoogle Scholar
  35. 35.
    Nakayama M, Kayagaki N, Yamaguchi N, Okumura K, Yagita H (2000) Involvement of TWEAK in interferon gamma-stimulated monocyte cytotoxicity. J Exp Med 192:1373–1380CrossRefPubMedGoogle Scholar
  36. 36.
    Naumann M, Nieters A, Hatada EN, Scheidereit C (1993) NF-kappa B precursor p100 inhibits nuclear translocation and DNA binding of NF-kappa B/rel-factors. Oncogene 8:2275–2281PubMedGoogle Scholar
  37. 37.
    Olsen TS, Hansen HE, Olsen HS (1985) Tubular ultrastructure in acute renal failure: alterations of cellular surfaces (brush-border and basolateral infoldings). Virchows Arch A Pathol Anat Histopathol 406:91–104CrossRefPubMedGoogle Scholar
  38. 38.
    Ortega A, Ramila D, Ardura JA, Esteban V, Ruiz-Ortega M, Barat A, Gazapo R, Bosch RJ, Esbrit P (2006) Role of parathyroid hormone-related protein in tubulointerstitial apoptosis and fibrosis after folic acid-induced nephrotoxicity. J Am Soc Nephrol 17:1594–1603CrossRefPubMedGoogle Scholar
  39. 39.
    Ortiz A, Bustos C, Alonso J, Alcazar R, Lopez-Armada MJ, Plaza JJ, Gonzalez E, Egido J (1995) Involvement of tumor necrosis factor-alpha in the pathogenesis of experimental and human glomerulonephritis. Adv Nephrol Necker Hosp 24:53–77PubMedGoogle Scholar
  40. 40.
    Ortiz A, Justo P, Catalan MP, Sanz AB, Lorz C, Egido J (2002) Apoptotic cell death in renal injury: the rationale for intervention. Curr Drug Targets Immune Endocr Metabol Disord 2:181–192CrossRefPubMedGoogle Scholar
  41. 41.
    Ortiz A, Justo P, Sanz A, Lorz C, Egido J (2003) Targeting apoptosis in acute tubular injury. Biochem Pharmacol 66:1589–1594CrossRefPubMedGoogle Scholar
  42. 42.
    Ortiz A, Lorz C, Catalan MP, Danoff TM, Yamasaki Y, Egido J, Neilson EG (2000) Expression of apoptosis regulatory proteins in tubular epithelium stressed in culture or following acute renal failure. Kidney Int 57:969–981CrossRefPubMedGoogle Scholar
  43. 43.
    Ortiz A, Lorz C, Egido J (1999) New kids in the block: the role of FasL and Fas in kidney damage. J Nephrol 12:150–158PubMedGoogle Scholar
  44. 44.
    Ortiz A, Lorz C, Gonzalez-Cuadrado S, Garcia del MR, O’Valle F, Egido J (1997) Cytokines and Fas regulate apoptosis in murine renal interstitial fibroblasts. J Am Soc Nephrol 8:1845–1854PubMedGoogle Scholar
  45. 45.
    Potrovita I, Zhang W, Burkly L, Hahm K, Lincecum J, Wang MZ, Maurer MH, Rossner M, Schneider A, Schwaninger M (2004) Tumor necrosis factor-like weak inducer of apoptosis-induced neurodegeneration. J Neurosci 24:8237–8244CrossRefPubMedGoogle Scholar
  46. 46.
    Saitoh T, Nakayama M, Nakano H, Yagita H, Yamamoto N, Yamaoka S (2003) TWEAK induces NF-kappaB2 p100 processing and long lasting NF-kappaB activation. J Biol Chem 278:36005–36012CrossRefPubMedGoogle Scholar
  47. 47.
    Sanz AB, Justo P, Sanchez-Nino MD, Blanco-Colio LM, Winkles JA, Kreztler M, Jakubowski A, Blanco J, Egido J, Ruiz-Ortega M, Ortiz A (2008a) The cytokine TWEAK modulates renal tubulointerstitial inflammation. J Am Soc Nephrol 19:695–703CrossRefPubMedGoogle Scholar
  48. 48.
    Sanz AB, Sanchez-Nino MD, Izquierdo MC, Jakubowski A, Justo P, Blanco-Colio LM, Ruiz-Ortega M, Egido J, Ortiz A (2009) TWEAK induces proliferation in renal tubular epithelium: a role in uninephrectomy-induced renal hyperplasia. J Cell Mol Med. 2009 May 1. [Epub ahead of print]Google Scholar
  49. 49.
    Sanz AB, Santamaria B, Ruiz-Ortega M, Egido J, Ortiz A (2008b) Mechanisms of renal apoptosis in health and disease. J Am Soc Nephrol 19:1634–1642CrossRefPubMedGoogle Scholar
  50. 50.
    Schwartz N, Su L, Burkly LC, Mackay M, Aranow C, Kollaros M, Michaelson JS, Rovin B, Putterman C (2006) Urinary TWEAK and the activity of lupus nephritis. J Autoimmun 27:242–250CrossRefPubMedGoogle Scholar
  51. 51.
    Solez K, Morel-Maroger L, Sraer JD (1979) The morphology of "acute tubular necrosis" in man: analysis of 57 renal biopsies and a comparison with the glycerol model. Medicine (Baltimore) 58:362–376Google Scholar
  52. 52.
    Sun J, Langer WJ, Devish K, Lane PH (2006) Compensatory kidney growth in estrogen receptor-alpha null mice. Am J Physiol Renal Physiol 290:F319–F323CrossRefPubMedGoogle Scholar
  53. 53.
    Tanabe K, Bonilla I, Winkles JA, Strittmatter SM (2003) Fibroblast growth factor-inducible-14 is induced in axotomized neurons and promotes neurite outgrowth. J Neurosci 23:9675–9686PubMedGoogle Scholar
  54. 54.
    Thurman JM (2007) Triggers of inflammation after renal ischemia/reperfusion. Clin Immunol 123:7–13CrossRefPubMedGoogle Scholar
  55. 55.
    Tran NL, McDonough WS, Savitch BA, Sawyer TF, Winkles JA, Berens ME (2005) The tumor necrosis factor-like weak inducer of apoptosis (TWEAK)-fibroblast growth factor-inducible 14 (Fn14) signaling system regulates glioma cell survival via NFkappaB pathway activation and BCL-XL/BCL-W expression. J Biol Chem 280:3483–3492CrossRefPubMedGoogle Scholar
  56. 56.
    van KC, Daha MR, van Es LA (1999) Tubular epithelial cells: A critical cell type in the regulation of renal inflammatory processes. Exp Nephrol 7:429–437CrossRefGoogle Scholar
  57. 57.
    Vince JE, Chau D, Callus B, Wong WW, Hawkins CJ, Schneider P, McKinlay M, Benetatos CA, Condon SM, Chunduru SK, Yeoh G, Brink R, Vaux DL, Silke J (2008) TWEAK-FN14 signaling induces lysosomal degradation of a cIAP1-TRAF2 complex to sensitize tumor cells to TNFalpha. J Cell Biol 182:171–184CrossRefPubMedGoogle Scholar
  58. 58.
    Webber EM, Bruix J, Pierce RH, Fausto N (1998) Tumor necrosis factor primes hepatocytes for DNA replication in the rat. Hepatology 28:1226–1234CrossRefPubMedGoogle Scholar
  59. 59.
    Winkles JA (2008) The TWEAK-Fn14 cytokine-receptor axis: discovery, biology and therapeutic targeting. Nat Rev Drug Discov 7:411–425CrossRefPubMedGoogle Scholar
  60. 60.
    Yamada Y, Webber EM, Kirillova I, Peschon JJ, Fausto N (1998) Analysis of liver regeneration in mice lacking type 1 or type 2 tumor necrosis factor receptor: requirement for type 1 but not type 2 receptor. Hepatology 28:959–970CrossRefPubMedGoogle Scholar
  61. 61.
    Zhao Z, Burkly LC, Campbell S, Schwartz N, Molano A, Choudhury A, Eisenberg RA, Michaelson JS, Putterman C (2007) TWEAK/Fn14 interactions are instrumental in the pathogenesis of nephritis in the chronic graft-versus-host model of systemic lupus erythematosus. J Immunol 179:7949–7958PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Ana Ortiz
    • 1
  • M.D. Sanchez-Niño
    • 1
  • M.C. Izquierdo
    • 1
  • L.M. Blanco-Colio
    • 1
  • R. Selgas
    • 2
  • M. Ruiz-Ortega
    • 1
  • J. Egido
    • 1
  • Ana B. Sanz
    • 3
  1. 1.Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Fundación Renal Iñigo Alvarez de ToledoMadridSpain
  2. 2.Servicio de Nefrologia, Fundación para la Investigación Biomédica del Hospital Universitario La Paz, Universidad Autónoma de Madrid, Fundación Renal Iñigo Alvarez de ToledoMadridSpain
  3. 3.Laboratory of NephrologyFundación para la Investigación Biomédica del Hospital Universitario La PazMadridSpain

Personalised recommendations