The TWEAK/Fn14 pathway as an aggravating and perpetuating factor in inflammatory diseases; focus on inflammatory bowel diseases

Journal of Leukocyte Biology

Volumn 92, Issue 2, 2012, Pages 265-279

  Dohi, Taeko ^a   Burkly, Linda C ^b  

^a NATIONAL CENTER FOR GLOBAL HEALTH AND MEDICINE   (Japan)

^b BIOGEN   (United States)

Author keywords

Crohn's disease; Epithelial death; Inflammation; Tissue remodeling; TNF superfamily; Ulcerative colitis

Indexed keywords

CYCLOOXYGENASE 2; CYTOKINE; CYTOKINE RECEPTOR; FN14 RECEPTOR; GAMMA INTERFERON; GROWTH FACTOR; I KAPPA B KINASE BETA; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INTERLEUKIN 10; INTERLEUKIN 13; INTERLEUKIN 17; INTERLEUKIN 1BETA; MATRIX METALLOPROTEINASE; MESSENGER RNA; MITOGEN ACTIVATED PROTEIN KINASE; MITOGEN ACTIVATED PROTEIN KINASE P38; RETINOIC ACID; STEROID; STRESS ACTIVATED PROTEIN KINASE; THYMIC STROMAL LYMPHOPOIETIN; TISSUE INHIBITOR OF METALLOPROTEINASE 1; TISSUE INHIBITOR OF METALLOPROTEINASE 2; TRANSFORMING GROWTH FACTOR BETA; TUMOR NECROSIS FACTOR ALPHA; TUMOR NECROSIS FACTOR ALPHA INHIBITOR; TUMOR NECROSIS FACTOR RECEPTOR ASSOCIATED FACTOR; TWEAK PROTEIN; UNCLASSIFIED DRUG;

ADAPTIVE IMMUNITY; APOPTOSIS; AUTOIMMUNE DISEASE; CELL DEATH; CELL DIFFERENTIATION; CELL INFILTRATION; CELL PROLIFERATION; CHRONIC INFLAMMATION; COLITIS; COLORECTAL CANCER; CROHN DISEASE; CYTOKINE PRODUCTION; DISEASE ASSOCIATION; DRUG EFFICACY; ENDOPLASMIC RETICULUM; ENTERITIS; FIBROBLAST; FIBROGENESIS; HISTOPATHOLOGY; HUMAN; IMMUNE SYSTEM; IN VITRO STUDY; IN VIVO STUDY; INCIDENCE; INFLAMMATORY DISEASE; LEUKOCYTE; LIVER FIBROSIS; LIVER INJURY; MEDIATOR; MORBIDITY; NONHUMAN; OSTEOPOROSIS; OXIDATIVE STRESS; PATHOPHYSIOLOGY; PRIORITY JOURNAL; PROGNOSIS; PROTEIN CLEAVAGE; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN LOCALIZATION; PROTEIN PROTEIN INTERACTION; PROTEIN SYNTHESIS; RECEPTOR UPREGULATION; REVIEW; RISK FACTOR; SIGNAL TRANSDUCTION; STEROID THERAPY; SURGICAL TECHNIQUE; TISSUE REGENERATION; TOTAL COLON RESECTION; TREATMENT INDICATION; ULCERATIVE COLITIS; WOUND HEALING;

AUTOIMMUNE DISEASES; HUMANS; INFLAMMATION; INFLAMMATORY BOWEL DISEASES; RECEPTORS, TUMOR NECROSIS FACTOR; SIGNAL TRANSDUCTION; TUMOR NECROSIS FACTORS;

EID: 84864749264     PISSN: 07415400     EISSN: None     Source Type: Journal    
DOI: 10.1189/jlb.0112042     Document Type: Review

References (110)

1. Burkly, L. C., Michaelson, J. S., Zheng, T. S. (2011) TWEAK/Fn14 pathway: an immunological switch for shaping tissue responses. Immunol. Rev. 244, 99-114.
2. Burkly, L. C., Dohi, T. (2011) The TWEAK/Fn14 pathway in tissue remodeling: for better or for worse. Adv. Exp. Med. Biol. 691, 305-322.
3. Burkly, L. C., Michaelson, J. S., Hahm, K., Jakubowski, A., Zheng, T. S. (2007) TWEAKing tissue remodeling by a multifunctional cytokine: role of TWEAK/Fn14 pathway in health and disease. Cytokine 40, 1-16.
4. Sanz, A. B., Sanchez-Niño, M. D., Ortiz, A. (2011) TWEAK, a multifunctional cytokine in kidney injury. Kidney Int. 80, 708-718.
5. Yepes, M. (2007) TWEAK and the central nervous system. Mol. Neuro-biol. 35, 255-265.
6. Zheng, T. S., Burkly, L. C. (2008) No end in site: TWEAK/Fn14 activation and autoimmunity associated- end-organ pathologies. J. Leukoc. Biol. 84, 338-347.
7. Michaelson, J. S., Burkly, L. C. (2009) Therapeutic targeting of TWEAK/Fnl4 in cancer: exploiting the intrinsic tumor cell killing capacity of the pathway. Results Probl. Cell Differ. 49, 145-160.
8. Winkles, J. A. (2008) The TWEAK-Fn14 cytokine-receptor axis: discovery, biology and therapeutic targeting. Nat. Rev. Drug Discov. 7, 411-425.
9. Bulek, K, Swaidani, S., Aronica, M., Li, X. (2010) Epithelium: the interplay between innate and Th2 immunity. Immunol. Cell Biol. 88, 257-268.
10. Saenz, S. A, Taylor, B. C, Artis, D. (2008) Welcome to the neighborhood: epithelial cell-derived cytokines license innate and adaptive immune responses at mucosal sites. Immunol. Rev. 226, 172-190.
11. Otte, J. M., Rosenberg, I. M., Podolsky, D. K (2003) Intestinal myofibroblasts in innate immune responses of the intestine. Gastroenterology 124,1866-1878.
12. Mifflin, R. C, Pinchuk, I. V., Saada, J. I., Powell, D. W. (2011) Intestinal myofibroblasts: targets for stem cell therapy. Am. J. Physiol. Gastroin-test. Liver Physiol. 300, G684-G696.
13. Chicheportiche, Y., Bourdon, P. R, Xu, H., Hsu, Y. M., Scott, H., Hes-sion, C, Garcia, I., Browning, J. L. (1997) TWEAK, a new secreted li-gand in the tumor necrosis factor family that weakly induces apoptosis. J. Biol. Chem. 272, 32401-32410.
14. 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, 931-944.
15. Desplat-Jego, S., Varriale, S., Creidy, R, Terra, R, Bernard, D., Khrest-chatisky, M., Izui, S., Chicheportiche, Y, Boucraut, J. (2002) TWEAK is expressed by glial cells, induces astrocyte proliferation and increases EAE severity.J. Neuroimmunol. 133, 116-123.
16. Donohue, P. J., Richards, C. M., Brown, S. A, Hanscom, H. N., Buschman, J., Thangada, S., Hla, T., Williams, M. S., Winkles, J. A. (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, 594-600.
17. Justo, P., Sanz, A. B., Sanchez-Niño, M. D., Winkles, J. A, Lorz, C, Egido, J., Ortiz, A. (2006) Cytokine cooperation in renal tubular cell injury: the role of TWEAK Kidney Int. 70, 1750-1758.
18. Dohi, T., Borodovsky, A, Wu, P., Shearstone, J. R, Kawashima, R, Runkel, L., Rajman, L., Dong, X., Scott, M. L., Michaelson, J. S., Jakubowski, A., Burkly, L. C. (2009) TWEAK/Fn14 pathway: a nonre-dundant role in intestinal damage in mice through a TWEAK/intestinal epithelial cell axis. Gastroenterology 136, 912-923.
19. Kawakita, T., Shiraki, K, Yamanaka, Y, Yamaguchi, Y, Saitou, Y, Eno-kimura, N., Yamamoto, N., Okano, H., Sugimoto, K, Murata, K, Na-kano, T. (2005) Functional expression of TWEAK in human colonic adenocarcinoma cells. Int. J. Oncol. 26, 87-93.
20. Nakayama, M., Kayagaki, N., Yamaguchi, N., Okumura, K, Yagita, H. (2000) Involvement of TWEAK in interferon 7-stimulated monocyte cytotoxicity. J. Exp. Med. 192, 1373-1380.
21. Neurath, M. F., Weigmann, B., Finotto, S., Glickman, J., Nieuwenhuis, E., Iijima, H., Mizoguchi, A, Mizoguchi, E., Mudter, J., Galle, P. R, Bhan, A, Autschbach, F., Sullivan, B. M., Szabo, S. J., Glimcher, L. H., Blumberg, R S. (2002) The transcription factor T-bet regulates mucosal T cell activation in experimental colitis and Crohn's disease. J. Exp. Med. 195, 1129-1143.
22. Parrello, T., Monteleone, G., Cucchiara, S., Monteleone, I., Sebkova, L., Doldo, P., Luzza, F., Pallone, F. (2000) Up-regulation of the IL-12 receptor /3 2 chain in Crohn's disease.J. Immunol. 165, 7234-7239.
23. Wiley, S. R., Cassiano, L., Lofton, T., Davis-Smith, T., Winkles, J. A, Lindner, V., Liu, H., Daniel, T. O., Smith, C. A, Fanslow, W. C. (2001) A novel TNF receptor family member binds TWEAK and is implicated in angiogenesis. Immunity 15, 837-846.
24. Meighan-Mantha, R L., Hsu, D. K, Guo, Y, Brown, S. A., Feng, S. L., Peifley, K A, Alberts, G. F., Copeland, N. G., Gilbert, D. J., Jenkins, N. A, Richards, C. M., Winkles, J. A. (1999) The mitogen-inducible Fn14 gene encodes a type I transmembrane protein that modulates fibroblast adhesion and migration. J. Biol. Chem. 274, 33166-33176.
25. Kim, S. H., Kang, Y J., Kim, W. J., Woo, D. K, Lee, Y, Kim, D. I., Park, Y.B., Kwon, B. S., Park, J. E., Lee, W. H. (2004) TWEAK can induce pro-inflammatory cytokines and matrix metalloproteinase-9 in macro phages. Circ. J. 68, 396-399.
26. Schapira, K, Burkly, L. C, Zheng, T. S., Wu, P., Groeneweg, M., Rousch, M., Kockx, M. M., Daemen, M. J., Heeneman, S. (2009) Fn14-Fc fusion protein regulates atherosclerosis in ApoE - /- mice and inhibits macrophage lipid uptake in vitro. Arterioscler. Thromb. Vasc. Biol. 29, 2021-2027.
27. Kawashima, R., Kawamura, Y I., Oshio, T., Son, A., Yamazaki, M., Hagi-wara, T., Okada, T., Inagaki-Ohara, K, Wu, P., Szak, S., Kawamura, Y.J., Konishi, F., Miyake, O., Yano, H., Saito, Y, Burkly, L. C, Dohi, T. (2011) Interleukin-13 damages intestinal mucosa via TWEAK and Fn14 in mice-a pathway associated with ulcerative colitis. Gastroenterology 141, 2119-2129.
28. Gao, H. X., Campbell, S. R., Burkly, L. C, Jakubowski, A., Jarchum, I., Banas, B., Saleem, M. A., Mathieson, P. W., Berman, J. W., Michaelson, J. S., Putterman, C. (2009) TNF-like weak inducer of apoptosis (TWEAK) induces inflammatory and proliferative effects in human kidney cells. Cytokine 46, 24-35.
29. Sanz, A. B., Sanchez-Niño, M. D., Izquierdo, M. C, Jakubowski, A, Justo, P., Blanco-Colio, L. M., 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. 13, 3329-3342.
30. Zimmermann, M., Koreck, A, Meyer, N., Basinski, T., Meiler, F., Si-mone, B., Woehrl, S., Moritz, K, Eiwegger, T., Schmid-Grendelmeier, P., Kemeny, L., Akdis, C. A. (2011) TNF-like weak inducer of apoptosis (TWEAK) and TNF-α cooperate in the induction of keratinocyte apoptosis. J. Allergy Clin. Immunol. 127, 200-207.
31. Jin, L., Nakao, A, Nakayama, M., Yamaguchi, N., Kojima, Y., Nakano, N., Tsuboi, R, Okumura, K, Yagita, H., Ogawa, H. (2004) Induction of RANTES by TWEAK/Fn14 interaction in human keratinocytes. J. Invest. Dermatol. 122, 1175-1179.
32. Brown, S. A., Richards, C. M., Hanscom, H. N., Feng, S. L., Winkles, J. A. (2003) The Fn14 cytoplasmic tail binds tumour-necrosis-factor-receptor-associated factors 1, 2, 3 and 5 and mediates nuclear factor-KB activation. Biochem. J. 371, 395-403.
33. Saitoh, T., Nakayama, M., Nakano, H., Yagita, H., Yamamoto, N., Yamaoka, S. (2003) TWEAK induces NF-κB2 p100 processing and long lasting NF-κB activation. J. Biol. Chem. 278, 36005-36012.
34. Brown, S. A., Ghosh, A, Winkles, J. A. (2010) Full-length, membrane-anchored TWEAK can function as a juxtacrine signaling molecule and activate the NF-κB pathway. J. Biol. Chem. 285, 17432-17441.
35. Roos, C, Wicovsky, A, Muller, N., Salzmann, S., Rosenthal, T., Kalthoff, H., Trauzold, A, Seher, A, Henkler, F., Kneitz, C, Wajant, H. (2010) Soluble and transmembrane TNF-like weak inducer of apopto sis differentially activate the classical and noncanonical NF-k B path way. J. Immunol. 185, 1593-1605.
36. Campbell, S., Burkly, L. C, Gao, H. X., Berman, J. W., Su, L., Browning, B., Zheng, T., Schiffer, L., Michaelson, J. S., Putterman, C. (2006) Proinflammatory effects of TWEAK/Fn14 interactions in glomerular mesangial cells. J. Immunol. 176, 1889-1898.
37. Hosokawa, Y, Hosokawa, I., Ozaki, K, Nakae, H., Matsuo, T. (2006) Proinflammatory effects of tumour necrosis factor-like weak inducer of apoptosis (TWEAK) on human gingival fibroblasts. Clin. Exp. Immunol. 146, 540-549.
38. Sanz, A. B., Justo, P., Sanchez-Niño, M. D., Blanco-Colio, L. M., Winkles, J. A, Kreztler, M., Jakubowski, A, Blanco, J., Egido, J., Ruiz-Ortega, M., Ortiz, A. (2008) The cytokine TWEAK modulates renal tubu-lointerstitial inflammation. J. Am. Soc. Nephrol. 19, 695-703.
39. Sanz, A. B., Sanchez-Niño, M. D., Izquierdo, M. C, Jakubowski, A, Justo, P., Blanco-Colio, L. M., Ruiz-Ortega, M., Selgas, R, Egido, J., Ortiz, A. (2010) TWEAK activates the non-canonical NFkB pathway in murine renal tubular cells: modulation of CCL21. PLoS One 5, e8955.
40. Scholzke, M. N., Rottinger, A, Murikinati, S., Gehrig, N., Leib, C, Schwaninger, M. (2011) TWEAK regulates proliferation and differentiation of adult neural progenitor cells. Mol. Cell. Neurosci. 46, 325-332.
41. Dogra, C, Changotra, H., Wedhas, N., Qin, X., Wergedal, J. E., Kumar, A. (2007) TNF-related weak inducer of apoptosis (TWEAK) is a potent skeletal muscle-wasting cytokine. FASEB J. 21, 1857-1869.
42. Li, H., Mittal, A, Makonchuk, D. Y, Bhatnagar, S., Kumar, A. (2009) Matrix metalloproteinase-9 inhibition ameliorates pathogenesis and improves skeletal muscle regeneration in muscular dystrophy. Hum. Mol. Genet. 18, 2584-2598.
43. Dai, L., Gu, L., Ding, C, Qiu, L., Di, W. (2009) TWEAK promotes ovarian cancer cell metastasis via NF-κB pathway activation and VEGF expression. Cancer Lett. 283, 159-167.
44. Willis, A. L., Tran, N. L., Chatigny, J. M., Charlton, N., Vu, H., Brown, S. A, Black, M. A, McDonough, W. S., Fortin, S. P., Niska, J. R, Winkles, J. A, Cunliffe, H. E. (2008) The fibroblast growth factor-inducible 14 receptor is highly expressed in HER2-positive breast tumors and regulates breast cancer cell invasive capacity. Mol. Cancer Res. 6, 725-734.
45. Tran, N. L., McDonough, W. S., Savitch, B. A, Sawyer, T. F., Winkles, J. A, Berens, M. E. (2005) The tumor necrosis factor-like weak inducer of apoptosis (TWEAK)-fibroblast growth factor-inducible 14 (Fn14) signaling system regulates glioma cell survival via NFkB pathway activation and BCL-XL/BCL-W expression. J. Biol. Chem. 280, 3483-3492.
46. Potrovita, I., Zhang, W., Burkly, L., Hahm, K, Lincecum, J., Wang, M. Z., Maurer, M. H., Rossner, M., Schneider, A, Schwaninger, M. (2004) Tumor necrosis factor-like weak inducer of apoptosis-induced neurodegeneration. J. Neurosci. 24, 8237-8244.
47. Dogra, C, Hall, S. L., Wedhas, N., Linkhart, T. A, Kumar, A. (2007) Fibroblast growth factor inducible 14 (Fn14) is required for the expression of myogenic regulatory factors and differentiation of myoblasts into myotubes. Evidence for TWEAK-independent functions of Fn14 during myogenesis. J. Biol. Chem. 282, 15000-15010.
48. Polavarapu, R., Gongora, M. C, Winkles, J. A, Yepes, M. (2005) Tumor necrosis factor-like weak inducer of apoptosis increases the permeability of the neurovascular unit through nuclear factor-K B pathway activation. J. Neurosci. 25, 10094-10100.
49. Atreya, I., Atreya, R, Neurath, M. F. (2008) NF-κB in inflammatory bowel disease. J. Intern. Med. 263, 591-596.
50. Wu, F., Chakravarti, S. (2007) Differential expression of inflammatory and fibrogenic genes and their regulation by NF-κB inhibition in a mouse model of chronic colitis. J. Immunol. 179, 6988-7000.
51. Karin, M. (2006) Nuclear factor-KB in cancer development and progression. Nature 441, 431-436.
52. Greten, F. R, Eckmann, L., Greten, T. F., Park, J. M., Li, Z. W., Egan, L. J., Kagnoff, M. F., Karin, M. (2004) IKKβ links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 118, 285-296.
53. Ando, T., Ichikawa, J., Wako, M., Hatsushika, K, Watanabe, Y, Sa-kuma, 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, R146.
54. Kumar, M., Makonchuk, D. Y, Li, H., Mittal, A, Kumar, A. (2009) TNF-like weak inducer of apoptosis (TWEAK) activates proinflammatory signaling pathways and gene expression through the activation of TGF-β-activated kinase 1. J. Immunol. 182, 2439-2448.
55. Novoyatleva, T., Diehl, F., van Amerongen, M. J., Patra, C, Ferrazzi, F., Bellazzi, R, Engel, F. B. (2010) TWEAK is a positive regulator of cardi-omyocyte proliferation. Cardiovasc. Res. 85, 681-690.
56. Vincent, C, Findlay, D. M., Welldon, K J., Wijenayaka, A. R, Zheng, T. S., Haynes, D. R, Fazzalari, N. L., Evdokiou, A, Atkins, G.J. (2009) Pro-inflammatory cytokines TNF-related weak inducer of apoptosis (TWEAK) and TNFα induce the mitogen-activated protein kinase (MAPK)-dependent expression of sclerostin in human osteoblasts. J. Bone Miner. Res. 24, 1434-1449.
57. Michaelson, J. S., Burkly, L. C. (2009) Therapeutic targeting of TWEAK/Fn14 in cancer: exploiting the intrinsic tumor cell killing capacity of the pathway. Results Probl. Cell Differ. 49, 145-160.
58. Haile, W. B., Echeverry, R, Wu, F., Guzman, J., An, J., Wu, J., Yepes, M. (2010) Tumor necrosis factor-like weak inducer of apoptosis and fibroblast growth factor-inducible 14 mediate cerebral ischemia-induced poly(ADP-ribose) polymerase-1 activation and neuronal death. Neuroscience 171, 1256-1264.
59. Michaelson, J. S., Amatucci, A, Kelly, R, Su, L., Garber, E., Day, E. S., Berquist, L., Cho, S., Li, Y, Parr, M., Wille, L., Schneider, P., Wortham, K, Burkly, L. C, Hsu, Y M., Joseph, I. B. (2011) Development of an Fn14 agonistic antibody as an anti-tumor agent. MAbs 3, 362-375.
60. 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, 734-743.
61. Nakayama, M., Ishidoh, K, Kojima, Y, Harada, N., Kominami, E., Okumura, K, Yagita, H. (2003) Fibroblast growth factor-inducible 14 mediates multiple pathways of TWEAK-induced cell death. J. Immunol. 170, 341-348.
62. Wang, D., Fung, J. N., Tuo, Y, Hu, L., Chen, C. (2010) TWEAK/Fn14 promotes apoptosis of human endometrial cancer cells via caspase pathway. Cancer Lett. 294, 91-100.
63. Ikner, A, Ashkenazi, A. (2011) TWEAK induces apoptosis through a death-signaling complex comprising receptor-interacting protein 1 (RIP1), Fas-associated death domain (FADD), and caspase-8. J. Biol. Chem. 286,21546-21554.
64. Vince, J. E., Chau, D., Callus, B., Wong, W. W., Hawkins, C. J., Schneider, P., McKinlay, M., Benetatos, C. A, Condon, S. M., Chunduru, S. K, Yeoh, G., Brink, R, Vaux, D. L., Silke, J. (2008) TWEAK-FN14 signaling induces lysosomal degradation of a cIAP1-TRAF2 complex to sensitize tumor cells to TNFα. J. Cell Biol. 182, 171-184.
65. Wicovsky, A., Salzmann, S., Roos, C, Ehrenschwender, M., Rosenthal, T., Siegmund, D., Henkler, F., Gohlke, F., Kneitz, C, Wajant, H. (2009) TNF-like weak inducer of apoptosis inhibits proinflammatory TNF receptor-1 signaling. Cell Death Differ. 16, 1445-1459.
66. Vandenabeele, P., Galluzzi, L., Vanden Berghe, T., Kroemer, G. (2010) Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat. Rev. Mol. Cell. Biol. 11, 700-714.
67. Gunther, C, Martini, E., Wittkopf, N., Amann, K, Weigmann, B., Neumann, H., Waldner, M. J., Hedrick, S. M., Tenzer, S., Neurath, M. F., Becker, C. (2011) Caspase-8 regulates TNF-α-induced epithelial necroptosis and terminal ileitis. Nature 477, 335-339.
68. Duprez, L., Takahashi, N., Van Hauwermeiren, F., Vandendriessche, B., Goossens, V, Vanden Berghe, T., Declercq, W., Libert, C, Cauwels, A, Vandenabeele, P. (2011) RIP kinase-dependent necrosis drives lethal systemic inflammatory response syndrome. Immunity 35, 908-918.
69. Hartupee, J., Liu, C, Novotny, M., Li, X., Hamilton, T. (2007) IL-17 enhances chemokine gene expression through mRNA stabilization. J. Immunol. 179, 4135-4141.
70. Han, E. S., Mekasha, S., Ingalls, R R (2010) Fibroblast growth factor-inducible 14 (Fn14) is expressed in the lower genital tract and may play a role in amplifying inflammation during infection. J. Reprod. Immunol. 84, 16-23.
71. Munoz-Garcia, B., Moreno, J. A., Lopez-Franco, O., Sanz, A. B., Martin-Ventura, J. L., Blanco, J., Jakubowski, A., Burkly, L. C., Ortiz, A., Egido, J., Blanco-Colio, L. M. (2009) Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) enhances vascular and renal damage induced by hyperlipidemic diet in ApoE-knockout mice. Arterioscler. Thromb. Vasc. Biol. 29, 2061-2068.
72. Bhatnagar, S., Mittal, A., Gupta, S. K., Kumar, A. (2012) TWEAK causes myotube atrophy through coordinated activation of ubiquitin-proteasome system, autophagy, and caspases. J. Cell. Physiol. 227, 1042-1051.
73. Tirnitz-Parker, J. E., Viebahn, C. S., Jakubowski, A., Klopcic, B. R., Olynyk, J. K., Yeoh, G. C., Knight, B. (2010) Tumor necrosis factor-like weak inducer of apoptosis is a mitogen for liver progenitor cells. Hepa-tology 52, 291-302.
74. Hotta, K., Sho, M., Yamato, I., Shimada, K., Harada, H., Akahori, T., Nakamura, S., Konishi, N., Yagita, H., Nonomura, K., Nakajima, Y. (2011) Direct targeting of fibroblast growth factor-inducible 14 protein protects against renal ischemia reperfusion injury. Kidney Int. 79, 179-188.
75. Jain, M., Jakubowski, A., Cui, L., Shi, J., Su, L., Bauer, M., Guan, J., Lim, C. C., Naito, Y., Thompson, J. S., Sam, F., Ambrose, C., Parr, M., Crowell, T., Lincecum, J. M., Wang, M. Z., Hsu, Y. M., Zheng, T. S., Michaelson, J. S., Liao, R., Burkly, L. C. (2009) A novel role for tumor necrosis factor-like weak inducer of apoptosis (TWEAK) in the development of cardiac dysfunction and failure. Circulation 119, 2058-2068.
76. Mittal, A., Bhatnagar, S., Kumar, A., Lach-Trifilieff, E., Wauters, S., Li, H., Makonchuk, D. Y., Glass, D. J. (2010) The TWEAK-Fn14 system is a critical regulator of denervation-induced skeletal muscle atrophy in mice. J. Cell Biol. 188, 833-849.
77. Laskin, D. L., Sunil, V. R., Gardner, C. R., Laskin, J. D. (2011) Macro-phages and tissue injury: agents of defense or destruction? Annu. Rev. Pharmacol. Toxicol. 51, 267-288.
78. 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, 15-23.
79. Mueller, A. M., 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, 55-65.
80. Iocca, H. A., Plant, S. R., Wang, Y., Runkel, L., O'Connor, B. P., Lund-smith, E. T., Hahm, K., van Deventer, H. W., Burkly, L. C., Ting, J. P. (2008) TNF superfamily member TWEAK exacerbates inflammation and demyelination in the cuprizone-induced model. J. Neuroimmunol. 194, 97-106.
81. Yepes, M., Brown, S. A., Moore, E. G., Smith, E. P., Lawrence, D. A., Winkles, J. A. (2005) A soluble Fn14-Fc decoy receptor reduces infarct volume in a murine model of cerebral ischemia. Am. J. Pathol. 166, 511-520.
82. Zhang, X., Winkles, J. A., Gongora, M. C., Polavarapu, R., Michaelson, J. S., Hahm, K., Burkly, L., Friedman, M., Li, X. J., Yepes, M. (2007) TWEAK-Fn14 pathway inhibition protects the integrity of the neurovas-cular unit during cerebral ischemia. J. Cereb. Blood Flow Metab. 27, 534-544.
83. Zhao, Z., Burkly, L. C., Campbell, S., Schwartz, N., Molano, A., Choud-hury, A., Eisenberg, R. A., Michaelson, J. S., Putterman, C. (2007) TWEAK/Fn14 interactions are instrumental in the pathogenesis of nephritis in the chronic graft-versus-host model of systemic lupus ery-thematosus. J. Immunol. 179, 7949-7958.
84. Izquierdo, M. C., Sanz, A. B., Mezzano, S., Blanco, J., Carrasco, S., San-chez-Niño, M. D., Benito-Martin, A., Ruiz-Ortega, M., Egido, J., Ortiz, A. (2012) TWEAK (tumor necrosis factor-like weak inducer of apopto-sis) activates CXCL16 expression during renal tubulointerstitial inflammation. Kidney Int. 81, 1098-1107.
85. Perper, S. J., Browning, B., Burkly, L. C., Weng, S., Gao, C., Giza, K., Su, L., Tarilonte, L., Crowell, T., Rajman, L., Runkel, L., Scott, M., Atkins, G. J., Findlay, D. M., Zheng, T. S., Hess, H. (2006) TWEAK is a novel arthritogenic mediator. J. Immunol. 177, 2610-2620.
86. 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, 6433-6439.
87. Asakura, K., Nishiwaki, Y., Inoue, N., Hibi, T., Watanabe, M., Take-bayashi, T. (2009) Prevalence of ulcerative colitis and Crohn's disease in Japan. J. Gastroenterol. 44, 659-665.
88. Leong, R. W., Kamm, M. A., Hu, P. J., Sung, J. J. (2010) Inflammatory bowel disease in Asia. J. Gastroenterol. Hepatol. 25, 436-438.
89. Tilg, H., Moschen, A. R., Kaser, A., Pines, A., Dotan, I. (2008) Gut, inflammation and osteoporosis: basic and clinical concepts. Gut 57, 684-694.
90. MacDonald, T. T., Monteleone, I., Fantini, M. C, Monteleone, G. (2011) Regulation of homeostasis and inflammation in the intestine. Gastroenterology 140, 1768-1775.
91. Hamilton, M. J., Snapper, S. B., Blumberg, R. S. (2012) Update on biologic pathways in inflammatory bowel disease and their therapeutic relevance. J Gastroenterol. 47, 1-8.
92. Khor, B., Gardet, A., Xavier, R J. (2011) Genetics and pathogenesis of inflammatory bowel disease. Nature 474, 307-317.
93. Strober, W., Fuss, I.J. (2011) Proinflammatory cytokines in the pathogenesis of inflammatory bowel diseases. Gastroenterology 140, 1756-1767.
94. McKenzie, S. J., Baker, M. S., Buffinton, G. D., Doe, W. F. (1996) Evid-nec of oxidant-induced injury to epithelial cells during inflammatory bowel disease. J. Clin. Invest. 98, 136-141.
95. Roessner, A., Kuester, D., Malfertheiner, P., Schneider-Stock, R (2008) Oxidative stress in ulcerative colitis-associated carcinogenesis. Pathol. Res. Pract. 204, 511-524.
96. Saenz, S. A, Noti, M., Artis, D. (2010) Innate immune cell populations function as initiators and effectors in Th2 cytokine responses. Trends Immunol. 31, 407-413.
97. Heller, F., Florian, P., Bojarski, C, Richter, J., Christ, M., Hillenbrand, B., Mankertz, J., Gitter, A. H., Burgel, N., Fromm, M., Zeitz, M., Fuss, I., Strober, W., Schulzke, J. D. (2005) Interleukin-13 is the key effector Th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution. Gastroenterology 129, 550-564.
98. Kawashima, R., Kawamura, Y. I., Kato, R, Mizutani, N., Toyama-Sorima-chi, N., Dohi, T. (2006) IL-13 receptor a2 promotes epithelial cell regeneration from radiation-induced small intestinal injury in mice. Gastroenterology 131, 130-141.
99. Bauer, C, Duewell, P., Mayer, C, Lehr, H. A, Fitzgerald, K. A, Dauer, M., Tschopp, J., Endres, S., Latz, E., Schnurr, M. (2010) Colitis induced in mice with dextran sulfate sodium (DSS) is mediated by the NLRP3 inflammasome. Gut 59, 1192-1199.
100. Dupaul-Chicoine, J., Yeretssian, G., Doiron, K, Bergstrom, K. S., McIn-tire, C. R, LeBlanc, P. M., Meunier, C, Turbide, C, Gros, P., Beauche-min, N., Vallance, B. A., Saleh, M. (2010) Control of intestinal homeostasis, colitis, and colitis-associated colorectal cancer by the inflammatory caspases. Immunity 32, 367-378.
101. Zaki, M. H., Boyd, K. L., Vogel, P., Kastan, M. B., Lamkanfi, M., Kanne-ganti, T. D. (2010) The NLRP3 inflammasome protects against loss of epithelial integrity and mortality during experimental colitis. Immunity 32, 379-391.
102. Heller, F., Fromm, A, Gitter, A. H., Mankertz, J., Schulzke, J. D. (2008) Epithelial apoptosis is a prominent feature of the epithelial barrier disturbance in intestinal inflammation: effect of pro-inflammatory interleukin-13 on epithelial cell function. Mucosal Immunol. 1 (Suppl. 1), S58-S61.
103. Brynskov, J., Foegh, P., Pedersen, G., Ellervik, C, Kirkegaard, T., Bingham, A, Saermark, T. (2002) Tumour necrosis factor a converting enzyme (TACE) activity in the colonic mucosa of patients with inflammatory bowel disease. Gut 51, 37-43.
104. Abraham, C, Medzhitov, R (2011) Interactions between the host innate immune system and microbes in inflammatory bowel disease. Gastroenterology 140, 1729-1737.
105. Andoh, A, Yasui, H., Inatomi, O., Zhang, Z., Deguchi, Y, Hata, K, Araki, Y, Tsujikawa, T., Kitoh, K, Kim-Mitsuyama, S., Takayanagi, A, Shimizu, N., Fujiyama, Y (2005) Interleukin-17 augments tumor necrosis factor-a-induced granulocyte and granulocyte/macrophage colony-stimulating factor release from human colonic myofibroblasts. J. Gastroenterol. 40, 802-810.
106. Kalinina, N., Agrotis, A, Antropova, Y, DiVitto, G., Kanellakis, P., Kos-tolias, G., Ilyinskaya, O., Tararak, E., Bobik, A. (2004) Increased expression of the DNA-binding cytokine HMGB1 in human atherosclerotic lesions: role of activated macrophages and cytokines. Arterioscler. Thromb. Vasc. Biol. 24, 2320-2325.
107. Vitali, R, Stronati, L., Negroni, A, Di Nardo, G., Pierdomenico, M., del Giudice, E., Rossi, P., Cucchiara, S. (2011) Fecal HMGB1 is a novel marker of intestinal mucosal inflammation in pediatric inflammatory bowel disease. Am. J. Gastroenterol. 106, 2029-2040.
108. Ravi, A, Garg, P., Sitaraman, S. V. (2007) Matrix metalloproteinases in inflammatory bowel disease: boon or a bane? Inflamm. Bowel Dis. 13, 97-107.
109. Hayden, D. M., Forsyth, C, Keshavarzian, A. (2011) The role of matrix metalloproteinases in intestinal epithelial wound healing during normal and inflammatory states. J. Surg. Res. 168, 315-324.
110. Chicheportiche, Y, Chicheportiche, R, Sizing, I., Thompson, J., Benjamin, C. B., Ambrose, C, Dayer, J. M. (2002) Proinflammatory activity of TWEAK on human dermal fibroblasts and synoviocytes: blocking and enhancing effects of anti-TWEAK monoclonal antibodies. Arthritis Res. 4, 126-133.