Skip to main content

Advertisement

SpringerLink
Log in

Tumor necrosis factor and lymphotoxin in regulation of intestinal inflammation

  • Review
  • Published:
Biochemistry (Moscow) Aims and scope Submit manuscript

Abstract

Ulcerative colitis and Crohn’s disease are the major forms of inflammatory bowel disease. Cytokines of the tumor necrosis factor (TNF) family play an important role in the regulation of intestinal inflammation. In this review, we discuss the function of key cytokines of this family–TNF and lymphotoxin (LT)–in mucosal healing, IgA production, and in control of innate lymphoid cells (ILCs), novel regulators of mucosal homeostasis in the gut. TNF plays a central role in the pathogenesis of inflammatory bowel diseases (IBD). LT regulates group 3 of ILCs and IL-22 production and protects the epithelium against damage by chemicals and mucosal bacterial pathogens. In addition, we discuss major mouse models employed to study the mechanism of intestinal inflammation, their advantages and limitations, as well as application of TNF blockers in the therapy for IBD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

CD:

Crohn’s disease

DCs:

dendritic cells

DSS:

dextran sulfate sodium

FDA:

Food and Drug Administration of USA

FDC:

follicular dendritic cells

GALT:

gut-associated lymphoid tissue

IBD:

inflammatory bowel disease

IFN:

interferon

IL:

interleukin

ILCs:

innate lymphoid cells

LIGHT:

homologous to lymphotoxin, exhibits inducible expression and competes with HSV glycoprotein D for binding to herpesvirus entry mediator, a receptor expressed on T-lymphocytes (another name: tumor necrosis factor superfamily member 14, TNFSF14)

LT:

lymphotoxin

LTßR:

membrane lymphotoxin receptor

MHC:

major histocompatibility complex

MNP:

mononuclear phagocytes

TACE:

TNF-alpha converting enzyme

TNBS:

2,4,6-trinitrobenzenesulfonic acid

TNF:

tumor necrosis factor

TNFR:

tumor necrosis factor receptor

UC:

ulcerative colitis

References

  1. Locksley, R. M., Killeen, N., and Lenardo, M. J. (2001) The TNF and TNF receptor superfamilies: integrating mammalian biology, Cell, 104, 487–501.

    Article  CAS  PubMed  Google Scholar 

  2. Ward-Kavanagh, L. K., Lin, W. W., Sedy, J. R., and Ware, C. F. (2016) The TNF receptor superfamily in co-stimulating and co-inhibitory responses, Immunity, 44, 10051019.

    Article  CAS  Google Scholar 

  3. Ware, C. F. (2005) Network communications: lymphotoxins, LIGHT, and TNF, Annu. Rev. Immunol., 23, 787–819.

    Article  CAS  PubMed  Google Scholar 

  4. Croft, M., Benedict, C. A., and Ware, C. F. (2013) Clinical targeting of the TNF and TNFR superfamilies, Nat. Rev. Drug Discov., 12, 147–168.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Browning, J. L., and French, L. E. (2002) Visualization of lymphotoxin-beta and lymphotoxin-beta receptor expression in mouse embryos, J. Immunol., 168, 5079–5087.

    Article  CAS  PubMed  Google Scholar 

  6. Fu, Y. X., and Chaplin, D. D. (1999) Development and maturation of secondary lymphoid tissues, Annu. Rev. Immunol., 17, 399–433.

    Article  CAS  PubMed  Google Scholar 

  7. Sudhamsu, J., Yin, J., Chiang, E. Y., Starovasnik, M. A., Grogan, J. L., and Hymowitz, S. G. (2013) Dimerization of LTbetaR by LTalpha1beta2 is necessary and sufficient for signal transduction, Proc. Natl. Acad. Sci. USA, 110, 1989619901.

    Article  CAS  Google Scholar 

  8. Faustman, D., and Davis, M. (2010) TNF receptor 2 pathway: drug target for autoimmune diseases, Nat. Rev. Drug Discov., 9, 482–493.

    Article  CAS  PubMed  Google Scholar 

  9. Steinberg, M. W., Cheung, T. C., and Ware, C. F. (2011) The signaling networks of the herpesvirus entry mediator (TNFRSF14) in immune regulation, Immunol. Rev., 244, 169–187.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Randall, T. D., Carragher, D. M., and Rangel-Moreno, J. (2008) Development of secondary lymphoid organs, Annu. Rev. Immunol., 26, 627–650.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. McCarthy, D. D., Summers-Deluca, L., Vu, F., Chiu, S., Gao, Y., and Gommerman, J. L. (2006) The lymphotoxin pathway: beyond lymph node development, Immunol. Res., 35, 41–54.

    Article  CAS  PubMed  Google Scholar 

  12. Lo, J. C., Wang, Y., Tumanov, A. V., Bamji, M., Yao, Z., Reardon, C. A., Getz, G. S., and Fu, Y. X. (2007) Lymphotoxin beta receptor-dependent control of lipid homeostasis, Science, 316, 285–288.

    Article  CAS  PubMed  Google Scholar 

  13. Tumanov, A. V., Christiansen, P. A., and Fu, Y.-X. (2007) The role of lymphotoxin receptor signaling in diseases, Curr. Mol. Med., 7, 567–578.

    Article  CAS  PubMed  Google Scholar 

  14. Haybaeck, J., Zeller, N., Wolf, M. J., Weber, A., Wagner, U., Kurrer, M. O., Bremer, J., Iezzi, G., Graf, R., Clavien, P. A., Thimme, R., Blum, H., Nedospasov, S. A., Zatloukal, K., Ramzan, M., Ciesek, S., Pietschmann, T., Marche, P. N., Karin, M., Kopf, M., Browning, J. L., Aguzzi, A., and Heikenwalder, M. (2009) A lymphotoxindriven pathway to hepatocellular carcinoma, Cancer Cell, 16, 295–308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Upadhyay, V., and Fu, Y. X. (2013) Lymphotoxin signalling in immune homeostasis and the control of microorganisms, Nat. Rev. Immunol., 13, 270–279.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kruglov, A. A., Grivennikov, S. I., Kuprash, D. V., Winsauer, C., Prepens, S., Seleznik, G. M., Eberl, G., Littman, D. R., Heikenwalder, M., Tumanov, A. V., and Nedospasov, S. A. (2013) Nonredundant function of soluble LTalpha3 produced by innate lymphoid cells in intestinal homeostasis, Science, 342, 1243–1246.

    Article  CAS  PubMed  Google Scholar 

  17. Macho-Fernandez, E., Koroleva, E. P., Spencer, C. M., Tighe, M., Torrado, E., Cooper, A. M., Fu, Y. X., and Tumanov, A. V. (2015) Lymphotoxin beta receptor signaling limits mucosal damage through driving IL-23 production by epithelial cells, Mucosal Immunol., 8, 403–413.

    Article  CAS  PubMed  Google Scholar 

  18. Tumanov, A. V., Grivennikov, S. I., Kruglov, A. A., Shebzukhov, Y. V., Koroleva, E. P., Piao, Y., Cui, C. Y., Kuprash, D. V., and Nedospasov, S. A. (2010) Cellular source and molecular form of TNF specify its distinct functions in organization of secondary lymphoid organs, Blood, 116, 3456–3464.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Nielsen, O. H., and Ainsworth, M. A. (2013) Tumor necrosis factor inhibitors for inflammatory bowel disease, New Engl. J. Med., 369, 754–762.

    Article  CAS  PubMed  Google Scholar 

  20. Winsauer, C., Kruglov, A. A., Chashchina, A. A., Drutskaya, M. S., and Nedospasov, S. A. (2014) Cellular sources of pathogenic and protective TNF and experimental strategies based on utilization of TNF humanized mice, Cytokine Growth Factor Rev., 25, 115–123.

    Article  CAS  PubMed  Google Scholar 

  21. Dothel, G., Vasina, V., Barbara, G., and De Ponti, F. (2013) Animal models of chemically induced intestinal inflammation: predictivity and ethical issues, Pharmacol. Ther., 139, 71–86.

    Article  CAS  PubMed  Google Scholar 

  22. DeVoss, J., and Diehl, L. (2014) Murine models of inflammatory bowel disease (IBD): challenges of modeling human disease, Toxicol. Pathol., 42, 99–110.

    Article  PubMed  Google Scholar 

  23. Jiminez, J. A., Uwiera, T. C., Douglas Inglis, G., and Uwiera, R. R. (2015) Animal models to study acute and chronic intestinal inflammation in mammals, Gut Pathog., 7, 29.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Mizoguchi, A., Takeuchi, T., Himuro, H., Okada, T., and Mizoguchi, E. (2016) Genetically engineered mouse models for studying inflammatory bowel disease, J. Pathol., 238, 205–219.

    Article  PubMed  Google Scholar 

  25. Danese, S., Fiocchi, C., and Panes, J. (2016) Drug development in IBD: from novel target identification to early clinical trials, Gut, 65, 1233–1239.

    Article  PubMed  Google Scholar 

  26. Jurjus, A. R., Khoury, N. N., and Reimund, J.-M. (2004) Animal models of inflammatory bowel disease, J. Pharmacol. Toxicol. Methods, 50, 81–92.

    Article  CAS  PubMed  Google Scholar 

  27. Vorobyov, G. I., and Khalif, I. L. (eds.) (2008) Nonspecific Inflammatory Bowel Disease [in Russian], Miklosh, Moscow.

    Google Scholar 

  28. Baumgart, D. C., and Sandborn, W. J. (2012) Crohn’s disease, Lancet, 380, 1590–1605.

    Article  PubMed  Google Scholar 

  29. Danese, S., and Fiocchi, C. (2011) Ulcerative colitis, New Engl. J. Med., 365, 1713–1725.

    Article  CAS  PubMed  Google Scholar 

  30. Zimmerman, Ya. S., Zimmerman, I. Ya., and Tretyakova, Yu. I. (2013) Ulcerative colitis and Crohn’s disease: modern concept. Part 1. Definition, terminology, occurrence, etiology and pathogensis, diagnostics, complications, classification, Klin. Med., 11, 27–33.

    Google Scholar 

  31. Zimmerman, Ya. S., Zimmerman, I. Ya., and Tretyakova, Yu. I. (2013) Ulcerative colitis and Crohn’s disease: modern concept. Part 2. Diagnostics and differentiation therapy, Klin. Med., 12, 9–16.

    Google Scholar 

  32. Kaser, A., Zeissig, S., and Blumberg, R. S. (2010) Inflammatory bowel disease, Annu. Rev. Immunol., 28, 573–621.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kaplan, G. G. (2015) The global burden of IBD: from 2015 to 2025, Nat. Rev. Gastroenterol. Hepatol., 12, 720–727.

    Article  PubMed  Google Scholar 

  34. Wallace, K. L., Zheng, L. B., Kanazawa, Y., and Shih, D. Q. (2014) Immunopathology of inflammatory bowel disease, World J. Gastroenterol., 20, 6–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Neurath, M. F. (2014) Cytokines in inflammatory bowel disease, Nat. Rev. Immunol., 14, 329–342.

    Article  CAS  PubMed  Google Scholar 

  36. Dalal, S. R., and Chang, E. B. (2014) The microbial basis of inflammatory bowel diseases, The J. Clin. Invest., 124, 4190–4196.

    Article  CAS  PubMed  Google Scholar 

  37. Khor, B., Gardet, A., and Xavier, R. J. (2011) Genetics and pathogenesis of inflammatory bowel disease, Nature, 474, 307–317.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Sheehan, D., Moran, C., and Shanahan, F. (2015) The microbiota in inflammatory bowel disease, J. Gastroenterol., 50, 495–507.

    Article  CAS  PubMed  Google Scholar 

  39. Wirtz, S., Neufert, C., Weigmann, B., and Neurath, M. F. (2007) Chemically induced mouse models of intestinal inflammation, Nat. Protoc., 2, 541–546.

    Article  CAS  PubMed  Google Scholar 

  40. Low, D., Nguyen, D. D., and Mizoguchi, E. (2013) Animal models of ulcerative colitis and their application in drug research, Drug Des. Devel. Ther., 7, 1341–1357.

    PubMed  PubMed Central  Google Scholar 

  41. Okayasu, I., Hatakeyama, S., Yamada, M., Ohkusa, T., Inagaki, Y., and Nakaya, R. (1990) A novel method in the induction of reliable experimental acute and chronic ulcerative colitis in mice, Gastroenterology, 98, 694–702.

    Article  CAS  PubMed  Google Scholar 

  42. Pers, M., and Cerar, A. (2012) Dextran sodium sulphate colitis mouse model: traps and tricks, J. Biomed. Biotechnol., 2012, 718617.

    Google Scholar 

  43. Chassaing, B., Aitken, J. D., Malleshappa, M., and VijayKumar, M. (2014) Dextran sulfate sodium (DSS)-induced colitis in mice, Curr. Protoc. Immunol., 104, Unit 15.25.

    Google Scholar 

  44. Te Velde, A. A., Verstege, M. I., and Hommes, D. W. (2006) Critical appraisal of the current practice in murine TNBSinduced colitis, Inflamm. Bowel Dis., 12, 995–999.

    Article  PubMed  Google Scholar 

  45. Motavallian-Naeini, A., Andalib, S., Rabbani, M., Mahzouni, P., Afsharipour, M., and Minaiyan, M. (2012) Validation and optimization of experimental colitis induction in rats using 2,4,6-trinitrobenzene sulfonic acid, Res. Pharm. Sci., 7, 159–169.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Ko, J.-K.-S., Lam, F.-Y.-L., and Cheung, A.-P.-L. (2005) Amelioration of experimental colitis by Astragalus membranaceus through anti-oxidation and inhibition of adhesion molecule synthesis, World J. Gastroenterol., 11, 5787–5794.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Heller, F., Fuss, I. J., Nieuwenhuis, E. E., Blumberg, R. S., and Strober, W. (2002) Oxazolone colitis, a Th2 colitis model resembling ulcerative colitis, is mediated by IL-13producing NK-T cells, Immunity, 17, 629–638.

    CAS  PubMed  Google Scholar 

  48. Collins, J. W., Keeney, K. M., Crepin, V. F., Rathinam, V. A., Fitzgerald, K. A., Finlay, B. B., and Frankel, G. (2014) Citrobacter rodentium: infection, inflammation and the microbiota, Nat. Rev. Microbiol., 12, 612–623.

    Article  CAS  Google Scholar 

  49. Koroleva, E. P., Halperin, S., Gubernatorova, E. O., Macho-Fernandez, E., Spencer, C. M., and Tumanov, A. V. (2015) Citrobacter rodentium-induced colitis: a robust model to study mucosal immune responses in the gut, J. Immunol. Methods, 421, 61–72.

    Article  CAS  PubMed  Google Scholar 

  50. Rivera-Nieves, J., Bamias, G., Vidrich, A., Marini, M., Pizarro, T. T., McDuffie, M. J., Moskaluk, C. A., Cohn, S. M., and Cominelli, F. (2003) Emergence of perianal fistulizing disease in the SAMP1/YitFc mouse, a spontaneous model of chronic ileitis, Gastroenterology, 124, 972–982.

    PubMed  Google Scholar 

  51. Matsumoto, S., Okabe, Y., Setoyama, H., Takayama, K., Ohtsuka, J., Funahashi, H., Imaoka, A., Okada, Y., and Umesaki, Y. (1998) Inflammatory bowel disease-like enteritis and caecitis in a senescence accelerated mouse P1/Yit strain, Gut, 43, 71–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Pizarro, T. T., Arseneau, K. O., Bamias, G., and Cominelli, F. (2003) Mouse models for the study of Crohn’s disease, Trends Mol. Med., 9, 218–222.

    Article  CAS  PubMed  Google Scholar 

  53. Kuhn, R., Lohler, J., Rennick, D., Rajewsky, K., and Muller, W. (1993) Interleukin-10-deficient mice develop chronic enterocolitis, Cell, 75, 263–274.

    Article  CAS  PubMed  Google Scholar 

  54. Keubler, L. M., Buettner, M., Hager, C., and Bleich, A. (2015) A multihit model: colitis lessons from the interleukin-10-deficient mouse, Inflamm. Bowel Dis., 21, 19671975.

    Article  Google Scholar 

  55. Kontoyiannis, D., Boulougouris, G., Manoloukos, M., Armaka, M., Apostolaki, M., Pizarro, T., Kotlyarov, A., Forster, I., Flavell, R., Gaestel, M., Tsichlis, P., Cominelli, F., and Kollias, G. (2002) Genetic dissection of the cellular pathways and signaling mechanisms in modeled tumor necrosis factor-induced Crohn’s-like inflammatory bowel disease, J. Exp. Med., 196, 1563–1574.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Leach, M. W., Bean, A. G., Mauze, S., Coffman, R. L., and Powrie, F. (1996) Inflammatory bowel disease in C.B17 scid mice reconstituted with the CD45RBhigh subset of CD4+ T-cells, Am. J. Pathol., 148, 1503–1515.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Ostanin, D. V., Bao, J., Koboziev, I., Gray, L., RobinsonJackson, S. A., Kosloski-Davidson, M., Price, V. H., and Grisham, M. B. (2009) T-cell transfer model of chronic colitis: concepts, considerations, and tricks of the trade, Am. J. Physiol. Gastrointest. Liver Physiol., 296, G135-146.

  58. Sadlack, B., Merz, H., Schorle, H., Schimpl, A., Feller, A. C., and Horak, I. (1993) Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene, Cell, 75, 253–261.

    Article  CAS  PubMed  Google Scholar 

  59. Baumgart, D. C., Olivier, W. A., Reya, T., Peritt, D., Rombeau, J. L., and Carding, S. R. (1998) Mechanisms of intestinal epithelial cell injury and colitis in interleukin 2 (IL2)-deficient mice, Cell Immunol., 187, 52–66.

    Article  CAS  PubMed  Google Scholar 

  60. Lee, E. G., Boone, D. L., Chai, S., Libby, S. L., Chien, M., Lodolce, J. P., and Ma, A. (2000) Failure to regulate TNFinduced NF-kappaB and cell death responses in A20-deficient mice, Science, 289, 2350–2354.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Hammer, G. E., Turer, E. E., Taylor, K. E., Fang, C. J., Advincula, R., Oshima, S., Barrera, J., Huang, E. J., Hou, B., Malynn, B. A., Reizis, B., DeFranco, A., Criswell, L. A., Nakamura, M. C., and Ma, A. (2011) Expression of A20 by dendritic cells preserves immune homeostasis and prevents colitis and spondyloarthritis, Nat. Immunol., 12, 1184–1193.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Mombaerts, P., Mizoguchi, E., Grusby, M. J., Glimcher, L. H., Bhan, A. K., and Tonegawa, S. (1993) Spontaneous development of inflammatory bowel disease in T-cell receptor mutant mice, Cell, 75, 274–282.

    Article  CAS  PubMed  Google Scholar 

  63. Nagatani, K., Wang, S., Llado, V., Lau, C. W., Li, Z., Mizoguchi, A., Nagler, C. R., Shibata, Y., Reinecker, H.C., Mora, J. R., and Mizoguchi, E. (2012) Chitin microparticles for the control of intestinal inflammation, Inflamm. Bowel Dis., 18, 1698–1710.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Nenci, A., Becker, C., Wullaert, A., Gareus, R., Van Loo, G., Danese, S., Huth, M., Nikolaev, A., Neufert, C., Madison, B., Gumucio, D., Neurath, M. F., and Pasparakis, M. (2007) Epithelial NEMO links innate immunity to chronic intestinal inflammation, Nature, 446, 557–561.

    Article  CAS  PubMed  Google Scholar 

  65. Watanabe, M., Ueno, Y., Yajima, T., Okamoto, S., Hayashi, T., Yamazaki, M., Iwao, Y., Ishii, H., Habu, S., Uehira, M., Nishimoto, H., Ishikawa, H., Hata, J., and Hibi, T. (1998) Interleukin 7 transgenic mice develop chronic colitis with decreased interleukin 7 protein accumulation in the colonic mucosa, J. Exp. Med., 187, 389402.

    Article  Google Scholar 

  66. Rath, H. C., Wilson, K. H., and Sartor, R. B. (1999) Differential induction of colitis and gastritis in HLA-B27 transgenic rats selectively colonized with Bacteroides vulgatus or Escherichia coli, Infect. Immun., 67, 2969–2974.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Rath, H. C. (2002) Role of commensal bacteria in chronic experimental colitis: lessons from the HLA-B27 transgenic rat, Pathobiology, 70, 131–138.

    Article  CAS  PubMed  Google Scholar 

  68. Peloquin, J. M., and Nguyen, D. D. (2013) The microbiota and inflammatory bowel disease: insights from animal models, Anaerobe, 24, 102–106.

    Article  CAS  PubMed  Google Scholar 

  69. Gkouskou, K. K., Deligianni, C., Tsatsanis, C., and Eliopoulos, A. G. (2014) The gut microbiota in mouse models of inflammatory bowel disease, Front. Cell. Infect. Microbiol., 4, 28.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Eri, R., McGuckin, M. A., and Wadley, R. (2012) T cell transfer model of colitis: a great tool to assess the contribution of T cells in chronic intestinal inflammation, Methods Mol. Biol., 844, 261–275.

    Article  CAS  PubMed  Google Scholar 

  71. Shouval, D. S., Ouahed, J., Biswas, A., Goettel, J. A., Horwitz, B. H., Klein, C., Muise, A. M., and Snapper, S. B. (2014) Interleukin 10 receptor signaling: master regulator of intestinal mucosal homeostasis in mice and humans, Adv. Immunol., 122, 177–210.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Koboziev, I., Jones-Hall, Y., Valentine, J. F., Webb, C. R., Furr, K. L., and Grisham, M. B. (2015) Use of humanized mice to study the pathogenesis of autoimmune and inflammatory diseases, Inflamm. Bowel Dis., 21, 1652–1673.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Sonnenberg, G. F., and Artis, D. (2015) Innate lymphoid cells in the initiation, regulation and resolution of inflammation, Nat. Med., 21, 698–708.

    CAS  Google Scholar 

  74. Eberl, G., Colonna, M., Di Santo, J. P., and McKenzie, A. N. (2015) Innate lymphoid cells: a new paradigm in immunology, Science, 348, aaa6566.

  75. Spits, H., and Cupedo, T. (2012) Innate lymphoid cells: emerging insights in development, lineage relationships, and function, Annu. Rev. Immunol., 30, 647–675.

    Article  CAS  Google Scholar 

  76. Diefenbach, A., Colonna, M., and Koyasu, S. (2014) Development, differentiation, and diversity of innate lymphoid cells, Immunity, 41, 354–365.

    CAS  PubMed  Google Scholar 

  77. Vivier, E., Van De Pavert, S. A., Cooper, M. D., and Belz, G. T. (2016) The evolution of innate lymphoid cells, Nat. Immunol., 17, 790–794.

    Article  CAS  PubMed  Google Scholar 

  78. Spits, H., Artis, D., Colonna, M., Diefenbach, A., Di Santo, J. P., Eberl, G., Koyasu, S., Locksley, R. M., McKenzie, A. N., Mebius, R. E., Powrie, F., and Vivier, E. (2013) Innate lymphoid cells–a proposal for uniform nomenclature, Nat. Rev. Immunol., 13, 145–149.

    Article  CAS  PubMed  Google Scholar 

  79. McKenzie, A. N., Spits, H., and Eberl, G. (2014) Innate lymphoid cells in inflammation and immunity, Immunity, 41, 366–374.

    Article  CAS  PubMed  Google Scholar 

  80. Klose, C. S., and Artis, D. (2016) Innate lymphoid cells as regulators of immunity, inflammation and tissue homeostasis, Nat. Immunol., 17, 765–774.

    CAS  PubMed  Google Scholar 

  81. Wang, Y., Koroleva, E. P., Kruglov, A. A., Kuprash, D. V., Nedospasov, S. A., Fu, Y. X., and Tumanov, A. V. (2010) Lymphotoxin beta receptor signaling in intestinal epithelial cells orchestrates innate immune responses against mucosal bacterial infection, Immunity, 32, 403–413.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Sawa, S., Lochner, M., Satoh-Takayama, N., Dulauroy, S., Berard, M., Kleinschek, M., Cua, D., Di Santo, J. P., and Eberl, G. (2011) RORgammat(+) innate lymphoid cells regulate intestinal homeostasis by integrating negative signals from the symbiotic microbiota, Nat. Immunol., 12, 320–326.

    Article  CAS  PubMed  Google Scholar 

  83. Eberl, G. (2012) Development and evolution of RORgammat+ cells in a microbe’s world, Immunol. Rev., 245, 177–188.

    Article  CAS  PubMed  Google Scholar 

  84. Sonnenberg, G. F., Monticelli, L. A., Alenghat, T., Fung, T. C., Hutnick, N. A., Kunisawa, J., Shibata, N., Grunberg, S., Sinha, R., Zahm, A. M., Tardif, M. R., Sathaliyawala, T., Kubota, M., Farber, D. L., Collman, R. G., Shaked, A., Fouser, L. A., Weiner, D. B., Tessier, P. A., Friedman, J. R., Kiyono, H., Bushman, F. D., Chang, K. M., and Artis, D. (2012) Innate lymphoid cells promote anatomical containment of lymphoid-resident commensal bacteria, Science, 336, 1321–1325.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Hepworth, M. R., Fung, T. C., Masur, S. H., Kelsen, J. R., McConnell, F. M., Dubrot, J., Withers, D. R., Hugues, S., Farrar, M. A., Reith, W., Eberl, G., Baldassano, R. N., Laufer, T. M., Elson, C. O., and Sonnenberg, G. F. (2015) Immune tolerance. Group 3 innate lymphoid cells mediate intestinal selection of commensal bacteria-specific CD4(+) T-cells, Science, 348, 1031–1035.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Goc, J., Hepworth, M. R., and Sonnenberg, G. F. (2016) Group 3 innate lymphoid cells: regulating host-commensal bacteria interactions in inflammation and cancer, Int. Immunol., 28, 43–52.

    CAS  PubMed  Google Scholar 

  87. Cording, S., Medvedovic, J., Aychek, T., and Eberl, G. (2016) Innate lymphoid cells in defense, immunopathology and immunotherapy, Nat. Immunol., 17, 755–757.

    CAS  PubMed  Google Scholar 

  88. Zheng, Y., Valdez, P. A., Danilenko, D. M., Hu, Y., Sa, S. M., Gong, Q., Abbas, A. R., Modrusan, Z., Ghilardi, N., De Sauvage, F. J., and Ouyang, W. (2008) Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens, Nat. Med., 14, 282–289.

    Article  CAS  PubMed  Google Scholar 

  89. Hernandez, P. P., Mahlakoiv, T., Yang, I., Schwierzeck, V., Nguyen, N., Guendel, F., Gronke, K., Ryffel, B., Holscher, C., Dumoutier, L., Renauld, J. C., Suerbaum, S., Staeheli, P., and Diefenbach, A. (2015) Interferonlambda and interleukin 22 act synergistically for the induction of interferon-stimulated genes and control of rotavirus infection, Nat. Immunol., 16, 698–707.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Vonarbourg, C., Mortha, A., Bui, V. L., Hernandez, P. P., Kiss, E. A., Hoyler, T., Flach, M., Bengsch, B., Thimme, R., Holscher, C., Honig, M., Pannicke, U., Schwarz, K., Ware, C. F., Finke, D., and Diefenbach, A. (2010) Regulated expression of nuclear receptor RORt confers distinct functional fates to NK cell receptorexpressing RORt(+) innate lymphocytes, Immunity, 33, 736–751.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Fuchs, A., Vermi, W., Lee, J. S., Lonardi, S., Gilfillan, S., Newberry, R. D., Cella, M., and Colonna, M. (2013) Intraepithelial type 1 innate lymphoid cells are a unique subset of IL-12and IL-15-responsive IFN-gamma-producing cells, Immunity, 38, 769–781.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Bernink, J. H., Peters, C. P., Munneke, M., Te Velde, A. A., Meijer, S. L., Weijer, K., Hreggvidsdottir, H. S., Heinsbroek, S. E., Legrand, N., Buskens, C. J., Bemelman, W. A., Mjosberg, J. M., and Spits, H. (2013) Human type 1 innate lymphoid cells accumulate in inflamed mucosal tissues, Nat. Immunol., 14, 221229.

    Article  CAS  Google Scholar 

  93. Bernink, J. H., Krabbendam, L., Germar, K., De Jong, E., Gronke, K., Kofoed-Nielsen, M., Munneke, J. M., Hazenberg, M. D., Villaudy, J., Buskens, C. J., Bemelman, W. A., Diefenbach, A., Blom, B., and Spits, H. (2015) Interleukin-12 and -23 control plasticity of CD127(+) group 1 and group 3 innate lymphoid cells in the intestinal lamina propria, Immunity, 43, 146–160.

    Article  CAS  PubMed  Google Scholar 

  94. Spencer, S. P., Wilhelm, C., Yang, Q., Hall, J. A., Bouladoux, N., Boyd, A., Nutman, T. B., Urban, J. F., Wang, J., Ramalingam, T. R., Bhandoola, A., Wynn, T. A., and Belkaid, Y. (2014) Adaptation of innate lymphoid cells to a micronutrient deficiency promotes type 2 barrier immunity, Science, 343, 432–437.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Zook, E. C., and Kee, B. L. (2016) Development of innate lymphoid cells, Nat. Immunol., 17, 775–782.

    Article  CAS  PubMed  Google Scholar 

  96. Koues, O. I., Collins, P. L., Cella, M., Robinette, M. L., Porter, S. I., Pyfrom, S. C., Payton, J. E., Colonna, M., and Oltz, E. M. (2016) Distinct gene regulatory pathways for human innate versus adaptive lymphoid cells, Cell, 165, 1134–1146.

    Article  CAS  PubMed  Google Scholar 

  97. Sonnenberg, G. F. (2016) Transcriptionally defining ILC heterogeneity in humans, Nat. Immunol., 17, 351–352.

    Article  CAS  PubMed  Google Scholar 

  98. Magri, G., Miyajima, M., Bascones, S., Mortha, A., Puga, I., Cassis, L., Barra, C. M., Comerma, L., Chudnovskiy, A., Gentile, M., Llige, D., Cols, M., Serrano, S., Arostegui, J. I., Juan, M., Yague, J., Merad, M., Fagarasan, S., and Cerutti, A. (2014) Innate lymphoid cells integrate stromal and immunological signals to enhance antibody production by splenic marginal zone B cells, Nat. Immunol., 15, 354–364.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Magri, G., and Cerutti, A. (2015) Role of group 3 innate lymphoid cells in antibody production, Curr. Opin. Immunol., 33, 36–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Hanash, A. M., Dudakov, J. A., Hua, G., O’Connor, M. H., Young, L. F., Singer, N. V., West, M. L., Jenq, R. R., Holland, A. M., Kappel, L. W., Ghosh, A., Tsai, J. J., Rao, U. K., Yim, N. L., Smith, O. M., Velardi, E., Hawryluk, E. B., Murphy, G. F., Liu, C., Fouser, L. A., Kolesnick, R., Blazar, B. R., and Van den Brink, M. R. (2012) Interleukin-22 protects intestinal stem cells from immunemediated tissue damage and regulates sensitivity to graft versus host disease, Immunity, 37, 339–350.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Dudakov, J. A., Hanash, A. M., and Van den Brink, M. R. (2015) Interleukin-22: immunobiology and pathology, Annu. Rev. Immunol., 33, 747–785.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Buonocore, S., Ahern, P. P., Uhlig, H. H., Ivanov, I. I., Littman, D. R., Maloy, K. J., and Powrie, F. (2010) Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology, Nature, 464, 1371–1375.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Geremia, A., Arancibia-Carcamo, C. V., Fleming, M. P., Rust, N., Singh, B., Mortensen, N. J., Travis, S. P., and Powrie, F. (2011) IL-23-responsive innate lymphoid cells are increased in inflammatory bowel disease, J. Exp. Med., 208, 1127–1133.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Geremia, A., Biancheri, P., Allan, P., Corazza, G. R., and Di Sabatino, A. (2014) Innate and adaptive immunity in inflammatory bowel disease, Autoimmun. Rev., 13, 3–10.

    Article  CAS  PubMed  Google Scholar 

  105. Withers, D. R., Hepworth, M. R., Wang, X., Mackley, E. C., Halford, E. E., Dutton, E. E., Marriott, C. L., Brucklacher-Waldert, V., Veldhoen, M., Kelsen, J., Baldassano, R. N., and Sonnenberg, G. F. (2016) Transient inhibition of ROR-gammat therapeutically limits intestinal inflammation by reducing TH17 cells and preserving group 3 innate lymphoid cells, Nat. Med., 22, 319–323.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Goldberg, R., Prescott, N., Lord, G. M., MacDonald, T. T., and Powell, N. (2015) The unusual suspects–innate lymphoid cells as novel therapeutic targets in IBD, Nat. Rev. Gastroenterol. Hepatol., 12, 271–283.

    Article  CAS  PubMed  Google Scholar 

  107. Tumanov, A. V., Koroleva, E. P., Guo, X., Wang, Y., Kruglov, A., Nedospasov, S., and Fu, Y. X. (2011) Lymphotoxin controls the IL-22 protection pathway in gut innate lymphoid cells during mucosal pathogen challenge, Cell Host Microbe, 10, 44–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Spahn, T. W., Maaser, C., Eckmann, L., Heidemann, J., Lugering, A., Newberry, R., Domschke, W., Herbst, H., and Kucharzik, T. (2004) The lymphotoxin-beta receptor is critical for control of murine Citrobacter rodentiuminduced colitis, Gastroenterology, 127, 1463.

    Article  CAS  PubMed  Google Scholar 

  109. Cerovic, V., Bain, C. C., Mowat, A. M., and Milling, S. W. (2014) Intestinal macrophages and dendritic cells: what’s the difference? Trends Immunol., 35, 270–277.

  110. Guilliams, M., Ginhoux, F., Jakubzick, C., Naik, S. H., Onai, N., Schraml, B. U., Segura, E., Tussiwand, R., and Yona, S. (2014) Dendritic cells, monocytes and macrophages: a unified nomenclature based on ontogeny, Nat. Rev. Immunol., 14, 571–578.

    CAS  PubMed  Google Scholar 

  111. Backhed, F., Ley, R. E., Sonnenburg, J. L., Peterson, D. A., and Gordon, J. I. (2005) Host-bacterial mutualism in the human intestine, Science, 307, 1915–1920.

    Article  PubMed  CAS  Google Scholar 

  112. Gensollen, T., Iyer, S. S., Kasper, D. L., and Blumberg, R. S. (2016) How colonization by microbiota in early life shapes the immune system, Science, 352, 539–544.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Caballero, S., and Pamer, E. G. (2015) Microbiota-mediated inflammation and antimicrobial defense in the intestine, Annu. Rev. Immunol., 33, 227–256.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Hamada, H., Hiroi, T., Nishiyama, Y., Takahashi, H., Masunaga, Y., Hachimura, S., Kaminogawa, S., Takahashi-Iwanaga, H., Iwanaga, T., Kiyono, H., Yamamoto, H., and Ishikawa, H. (2002) Identification of multiple isolated lymphoid follicles on the antimesenteric wall of the mouse small intestine, J. Immunol., 168, 57–64.

    Article  CAS  PubMed  Google Scholar 

  115. Mantis, N. J., McGuinness, C. R., Sonuyi, O., Edwards, G., and Farrant, S. A. (2006) Immunoglobulin A antibodies against ricin A and B subunits protect epithelial cells from ricin intoxication, Infect. Immun., 74, 3455–3462.

  116. Pabst, O. (2012) New concepts in the generation and functions of IgA, Nat. Rev. Immunol., 12, 821–832.

    Article  CAS  PubMed  Google Scholar 

  117. Bemark, M., Boysen, P., and Lycke, N. Y. (2012) through T cell-dependent and T-cell-independent pathways, Ann. N. Y. Acad. Sci., 1247, 97–116.

  118. Cerutti, A. (2008) The regulation of IgA class switching, Nat. Rev. Immunol., 8, 421–434.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Gutzeit, C., Magri, G., and Cerutti, A. (2014) Intestinal IgA production and its role in host-microbe interaction, Immunol. Rev., 260, 76–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Fagarasan, S., Kawamoto, S., Kanagawa, O., and Suzuki, K. (2010) Adaptive immune regulation in the gut: T-celldependent and T-cell-independent IgA synthesis, Annu. Rev. Immunol., 28, 243–273.

    Article  CAS  PubMed  Google Scholar 

  121. Masahata, K., Umemoto, E., Kayama, H., Kotani, M., Nakamura, S., Kurakawa, T., Kikuta, J., Gotoh, K., Motooka, D., Sato, S., Higuchi, T., Baba, Y., Kurosaki, T., Kinoshita, M., Shimada, Y., Kimura, T., Okumura, R., Takeda, A., Tajima, M., Yoshie, O., Fukuzawa, M., Kiyono, H., Fagarasan, S., Iida, T., Ishii, M., and Takeda, K. (2014) Generation of colonic IgA-secreting cells in the caecal patch, Nat. Commun., 5, 3704.

    Article  PubMed  CAS  Google Scholar 

  122. Macpherson, A. J., Gatto, D., Sainsbury, E., Harriman, G. R., Hengartner, H., and Zinkernagel, R. M. (2000) A primitive T-cell-independent mechanism of intestinal mucosal IgA responses to commensal bacteria, Science, 288, 2222–2226.

    Article  CAS  PubMed  Google Scholar 

  123. Mora, J. R., Iwata, M., Eksteen, B., Song, S. Y., Junt, T., Senman, B., Otipoby, K. L., Yokota, A., Takeuchi, H., Ricciardi-Castagnoli, P., Rajewsky, K., Adams, D. H., and Von Andrian, U. H. (2006) Generation of gut-homing IgA-secreting B cells by intestinal dendritic cells, Science, 314, 1157–1160.

    Article  CAS  PubMed  Google Scholar 

  124. Lorenz, R. G., Chaplin, D. D., McDonald, K. G., McDonough, J. S., and Newberry, R. D. (2003) Isolated lymphoid follicle formation is inducible and dependent upon lymphotoxin-sufficient B lymphocytes, lymphotoxin beta receptor, and TNF receptor I function, J. Immunol., 170, 5475–5482.

    CAS  Google Scholar 

  125. Van De Pavert, S. A., and Mebius, R. E. (2010) New insights into the development of lymphoid tissues, Nat. Rev. Immunol., 10, 664–674.

    Article  PubMed  CAS  Google Scholar 

  126. Bar-Ephraim, Y. E., and Mebius, R. E. (2016) Innate lymphoid cells in secondary lymphoid organs, Immunol. Rev., 271, 185–199.

    Article  CAS  PubMed  Google Scholar 

  127. Kuprash, D. V., Tumanov, A. V., Liepinsh, D. J., Koroleva, E. P., Drutskaya, M. S., Kruglov, A. A., Shakhov, A. N., Southon, E., Murphy, W. J., Tessarollo, L., Grivennikov, S. I., and Nedospasov, S. A. (2005) Novel tumor necrosis factor-knockout mice that lack Peyer’s patches, Eur. J. Immunol., 35, 1592–1600.

    Article  CAS  PubMed  Google Scholar 

  128. Kang, H. S., Chin, R. K., Wang, Y., Yu, P., Wang, J., Newell, K. A., and Fu, Y. X. (2002) Signaling via LTbetaR on the lamina propria stromal cells of the gut is required for IgA production, Nat. Immunol., 3, 576–582.

    Article  CAS  PubMed  Google Scholar 

  129. Danese, S., and Peyrin-Biroulet, L. (2014) IBD in 2013: enriching the therapeutic armamentarium for IBD, Nat. Rev. Gastroenterol. Hepatol., 11, 84–86.

    Article  CAS  PubMed  Google Scholar 

  130. Rogler, G. (2015) Where are we heading to in pharmacological IBD therapy? Pharmacol. Res., 100, 220–227.

  131. Scharl, M., and Rogler, G. (2012) Inflammatory bowel disease pathogenesis: what is new? Curr. Opin. Gastroenterol., 28, 301–309.

  132. Bosani, M., Ardizzone, S., and Porro, G. B. (2009) Biologic targeting in the treatment of inflammatory bowel diseases, Biologics, 3, 77–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Olesen, C. M., Coskun, M., Peyrin-Biroulet, L., and Nielsen, O. H. (2016) Mechanisms behind efficacy of tumor necrosis factor inhibitors in inflammatory bowel diseases, Pharmacol. Ther., 159, 110–119.

    Article  CAS  PubMed  Google Scholar 

  134. Murch, S. H., Lamkin, V. A., Savage, M. O., WalkerSmith, J. A., and MacDonald, T. T. (1991) Serum concentrations of tumour necrosis factor alpha in childhood chronic inflammatory bowel disease, Gut, 32, 913–917.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Breese, E. J., Michie, C. A., Nicholls, S. W., Murch, S. H., Williams, C. B., Domizio, P., Walker-Smith, J. A., and MacDonald, T. T. (1994) Tumor necrosis factor alpha-producing cells in the intestinal mucosa of children with inflammatory bowel disease, Gastroenterology, 106, 1455–1466.

    Article  CAS  PubMed  Google Scholar 

  136. Nilsen, E. M., Johansen, F. E., Kvale, D., Krajci, P., and Brandtzaeg, P. (1999) Different regulatory pathways employed in cytokine-enhanced expression of secretory component and epithelial HLA class I genes, Eur. J. Immunol., 29, 168–179.

    Article  CAS  PubMed  Google Scholar 

  137. D’Haens, G. (2010) Anti-TNF treatment in Crohn’s disease: toward tailored therapy? Am. J. Gastroenterol., 105, 1140–1141.

  138. Tracey, D., Klareskog, L., Sasso, E. H., Salfeld, J. G., and Tak, P. P. (2008) Tumor necrosis factor antagonist mechanisms of action: a comprehensive review, Pharmacol. Ther., 117, 244–279.

    Article  CAS  PubMed  Google Scholar 

  139. Ueda, N., Tsukamoto, H., Mitoma, H., Ayano, M., Tanaka, A., Ohta, S., Inoue, Y., Arinobu, Y., Niiro, H., Akashi, K., and Horiuchi, T. (2013) The cytotoxic effects of certolizumab pegol and golimumab mediated by transmembrane tumor necrosis factor alpha, Inflamm. Bowel Dis., 19, 1224–1231.

    Article  PubMed  Google Scholar 

  140. Slevin, S. M., and Egan, L. J. (2015) New insights into the mechanisms of action of anti-tumor necrosis factor-alpha monoclonal antibodies in inflammatory bowel disease, Inflamm. Bowel Dis., 21, 2909–2920.

    Article  PubMed  Google Scholar 

  141. Shchigoleva, N. E., Matina, I. A., Ponomariova, A. P., Karpina, L. M., and Bologov, A. A. (2010) Use of infliximab in children with inflammatory bowel diseases, Pediatr. Pharmacol., 7, 55–61.

    Google Scholar 

  142. Benucci, M., Saviola, G., Manfredi, M., Sarzi-Puttini, P., and Atzeni, F. (2012) Tumor necrosis factors blocking agents: analogies and differences, Acta Biomed., 83, 72–80.

    CAS  PubMed  Google Scholar 

  143. Thorlund, K., Druyts, E., Toor, K., and Mills, E. J. (2015) Comparative efficacy of golimumab, infliximab, and adalimumab for moderately to severely active ulcerative colitis: a network meta-analysis accounting for differences in trial designs, Expert. Rev. Gastroenterol. Hepatol., 9, 693–700.

    CAS  PubMed  Google Scholar 

  144. Peake, S. T., Bernardo, D., Mann, E. R., Al-Hassi, H. O., Knight, S. C., and Hart, A. L. (2013) Mechanisms of action of anti-tumor necrosis factor alpha agents in Crohn’s disease, Inflamm. Bowel Dis., 19, 1546–1555.

    Article  PubMed  Google Scholar 

  145. Steenholdt, C., Brynskov, J., Thomsen, O. O., Munck, L. K., Fallingborg, J., Christensen, L. A., Pedersen, G., Kjeldsen, J., Jacobsen, B. A., Oxholm, A. S., Kjellberg, J., Bendtzen, K., and Ainsworth, M. A. (2014) Individualised therapy is more cost-effective than dose intensification in patients with Crohn’s disease who lose response to anti-TNF treatment: a randomised, controlled trial, Gut, 63, 919–927.

    PubMed  Google Scholar 

  146. Kaymakcalan, Z., Sakorafas, P., Bose, S., Scesney, S., Xiong, L., Hanzatian, D. K., Salfeld, J., and Sasso, E. H. (2009) Comparisons of affinities, avidities, and complement activation of adalimumab, infliximab, and etanercept in binding to soluble and membrane tumor necrosis factor, Clin. Immunol., 131, 308–316.

    CAS  PubMed  Google Scholar 

  147. Shealy, D. J., Cai, A., Staquet, K., Baker, A., Lacy, E. R., Johns, L., Vafa, O., Gunn, G., 3rd, Tam, S., Sague, S., Wang, D., Brigham-Burke, M., Dalmonte, P., Emmell, E., Pikounis, B., Bugelski, P. J., Zhou, H., Scallon, B. J., and Giles-Komar, J. (2010) Characterization of golimumab, a human monoclonal antibody specific for human tumor necrosis factor alpha, MAbs, 2, 428–439.

    PubMed  Google Scholar 

  148. Scallon, B., Cai, A., Solowski, N., Rosenberg, A., Song, X. Y., Shealy, D., and Wagner, C. (2002) Binding and functional comparisons of two types of tumor necrosis factor antagonists, J. Pharmacol. Exp. Ther., 301, 418–426.

    Article  CAS  PubMed  Google Scholar 

  149. Nesbitt, A., Fossati, G., Bergin, M., Stephens, P., Stephens, S., Foulkes, R., Brown, D., Robinson, M., and Bourne, T. (2007) Mechanism of action of certolizumab pegol (CDP870): in vitro comparison with other antitumor necrosis factor alpha agents, Inflamm. Bowel Dis., 13, 1323–1332.

    Article  PubMed  Google Scholar 

  150. Vos, A. C., Wildenberg, M. E., Arijs, I., Duijvestein, M., Verhaar, A. P., De Hertogh, G., Vermeire, S., Rutgeerts, P., Van den Brink, G. R., and Hommes, D. W. (2012) Regulatory macrophages induced by infliximab are involved in healing in vivo and in vitro, Inflamm. Bowel Dis., 18, 401–408.

    Article  PubMed  Google Scholar 

  151. Perrier, C., De Hertogh, G., Cremer, J., Vermeire, S., Rutgeerts, P., Van Assche, G., Szymkowski, D. E., and Ceuppens, J. L. (2013) Neutralization of membrane TNF, but not soluble TNF, is crucial for the treatment of experimental colitis, Inflamm. Bowel Dis., 19, 246–253.

    PubMed  Google Scholar 

  152. Oikonomopoulos, A., Van Deen, W. K., and Hommes, D. W. (2013) Anti-TNF antibodies in inflammatory bowel disease: do we finally know how it works? Curr. Drug Targets, 14, 1421–1432.

    Article  CAS  PubMed  Google Scholar 

  153. Sandborn, W. J., Hanauer, S. B., Katz, S., Safdi, M., Wolf, D. G., Baerg, R. D., Tremaine, W. J., Johnson, T., Diehl, N. N., and Zinsmeister, A. R. (2001) Etanercept for active Crohn’s disease: a randomized, double-blind, placebocontrolled trial, Gastroenterology, 121, 1088–1094.

    CAS  Google Scholar 

  154. Van den Brande, J. M., Braat, H., Van den Brink, G. R., Versteeg, H. H., Bauer, C. A., Hoedemaeker, I., Van Montfrans, C., Hommes, D. W., Peppelenbosch, M. P., and Van Deventer, S. J. (2003) Infliximab but not etanercept induces apoptosis in lamina propria T-lymphocytes from patients with Crohn’s disease, Gastroenterology, 124, 1774–1785.

    Article  PubMed  CAS  Google Scholar 

  155. Mocci, G., Marzo, M., Papa, A., Armuzzi, A., and Guidi, L. (2013) Dermatological adverse reactions during antiTNF treatments: focus on inflammatory bowel disease, J. Crohn’s Colitis, 7, 769–779.

    Article  Google Scholar 

  156. Targownik, L. E., and Bernstein, C. N. (2013) Infectious and malignant complications of TNF inhibitor therapy in IBD, Am. J. Gastroenterol., 108, 1835–1842, quiz 1843.

    Article  CAS  PubMed  Google Scholar 

  157. Cleynen, I., and Vermeire, S. (2012) Paradoxical inflammation induced by anti-TNF agents in patients with IBD, Nat. Rev. Gastroenterol. Hepatol., 9, 496–503.

    Article  CAS  PubMed  Google Scholar 

  158. Wiens, A., Venson, R., Correr, C. J., Otuki, M. F., and Pontarolo, R. (2010) Meta-analysis of the efficacy and safety of adalimumab, etanercept, and infliximab for the treatment of rheumatoid arthritis, Pharmacotherapy, 30, 339–353.

    CAS  PubMed  Google Scholar 

  159. Heldmann, F., Brandt, J., Van der Horst-Bruinsma, I. E., Landewe, R., Sieper, J., Burmester, G. R., Van den Bosch, F., De Vlam, K., Geusens, P., Gaston, H., Schewe, S., Appelboom, T., Emery, P., Dougados, M., Leirisalo-Repo, M., Breban, M., Listing, J., and Braun, J. (2011) The European ankylosing spondylitis infliximab cohort (EASIC): a European multicentre study of long term outcomes in patients with ankylosing spondylitis treated with infliximab, Clin. Exp. Rheumatol., 29, 672–680.

    CAS  PubMed  Google Scholar 

  160. Tzu, J., and Kerdel, F. (2008) From conventional to cutting edge: the new era of biologics in treatment of psoriasis, Dermatol. Ther., 21, 131–141.

    Article  PubMed  Google Scholar 

  161. Angelucci, E., Cocco, A., Viscido, A., Vernia, P., and Caprilli, R. (2007) Another paradox in Crohn’s disease: new onset of psoriasis in a patient receiving tumor necrosis factor-alpha antagonist, Inflamm. Bowel Dis., 13, 10591061.

    Article  Google Scholar 

  162. Cullen, G., Kroshinsky, D., Cheifetz, A. S., and Korzenik, J. R. (2011) Psoriasis associated with anti-tumour necrosis factor therapy in inflammatory bowel disease: a new series and a review of 120 cases from the literature, Aliment. Pharmacol. Ther., 34, 1318–1327.

    Article  CAS  PubMed  Google Scholar 

  163. Palucka, A. K., Blanck, J. P., Bennett, L., Pascual, V., and Banchereau, J. (2005) Cross-regulation of TNF and IFNalpha in autoimmune diseases, Proc. Natl. Acad. Sci. USA, 102, 3372–3377.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Williams, V. L., and Cohen, P. R. (2011) TNF alpha antagonist-induced lupus-like syndrome: report and review of the literature with implications for treatment with alternative TNF alpha antagonists, Int. J. Dermatol., 50, 619–625.

    Article  PubMed  Google Scholar 

  165. Bout-Tabaku, S., Rivas-Chacon, R., and Restrepo, R. (2007) Systemic lupus erythematosus in a patient treated with etanercept for polyarticular juvenile rheumatoid arthritis, J. Rheumatol., 34, 2503–2504.

    PubMed  Google Scholar 

  166. Ferraccioli, G., Mecchia, F., Di Poi, E., and Fabris, M. (2002) Anticardiolipin antibodies in rheumatoid patients treated with etanercept or conventional combination therapy: direct and indirect evidence for a possible association with infections, Ann. Rheum. Dis., 61, 358–361.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Via, C. S., Shustov, A., Rus, V., Lang, T., Nguyen, P., and Finkelman, F. D. (2001) In vivo neutralization of TNFalpha promotes humoral autoimmunity by preventing the induction of CTL, J. Immunol., 167, 6821–6826.

    Article  CAS  PubMed  Google Scholar 

  168. Fidder, H., Schnitzler, F., Ferrante, M., Noman, M., Katsanos, K., Segaert, S., Henckaerts, L., Van Assche, G., Vermeire, S., and Rutgeerts, P. (2009) Long-term safety of infliximab for the treatment of inflammatory bowel disease: a single-centre cohort study, Gut, 58, 501–508.

    Article  CAS  PubMed  Google Scholar 

  169. Hochman, D., and Wolff, B. (2006) Risk of serious infections and malignancies with anti-TNF antibody therapy in rheumatoid arthritis, JAMA, 296, 2203; author reply 2203-2204.

    Article  CAS  PubMed  Google Scholar 

  170. Stern, R. S., Liebman, E. J., and Vakeva, L. (1998) Oral psoralen and ultraviolet-A light (PUVA) treatment of psoriasis and persistent risk of nonmelanoma skin cancer. PUVA Follow-up Study, J. Natl. Cancer Inst., 90, 1278–1284.

    Article  CAS  PubMed  Google Scholar 

  171. Peyrin-Biroulet, L., Khosrotehrani, K., Carrat, F., Bouvier, A. M., Chevaux, J. B., Simon, T., Carbonnel, F., Colombel, J. F., Dupas, J. L., Godeberge, P., Hugot, J. P., Lemann, M., Nahon, S., Sabate, J. M., Tucat, G., and Beaugerie, L. (2011) Increased risk for nonmelanoma skin cancers in patients who receive thiopurines for inflammatory bowel disease, Gastroenterology, 141, 1621–1628.

    Article  CAS  PubMed  Google Scholar 

  172. Steenholdt, C., Svenson, M., Bendtzen, K., Thomsen, O. O., Brynskov, J., and Ainsworth, M. A. (2011) Severe infusion reactions to infliximab: aetiology, immunogenicity and risk factors in patients with inflammatory bowel disease, Aliment. Pharmacol. Ther., 34, 51–58.

    CAS  PubMed  Google Scholar 

  173. Slifman, N. R., Gershon, S. K., Lee, J. H., Edwards, E. T., and Braun, M. M. (2003) Listeria monocytogenes infection as a complication of treatment with tumor necrosis factor alpha-neutralizing agents, Arthritis. Rheum., 48, 319–324.

    Article  CAS  PubMed  Google Scholar 

  174. Peyrin-Biroulet, L., Deltenre, P., De Suray, N., Branche, J., Sandborn, W. J., and Colombel, J. F. (2008) Efficacy and safety of tumor necrosis factor antagonists in Crohn’s disease: meta-analysis of placebo-controlled trials, Clin. Gastroenterol. Hepatol., 6, 644–653.

    Article  CAS  PubMed  Google Scholar 

  175. Shebzukhov, Y. V., Kuchmiy, A. A., Kruglov, A. A., Zipp, F., Siffrin, V., and Nedospasov, S. A. (2014) Experimental applications of TNF-reporter mice with far-red fluorescent label, Methods Mol. Biol., 1155, 151–162.

    Article  PubMed  Google Scholar 

  176. Lowenberg, M., and D’Haens, G. (2015) Next-generation therapeutics for IBD, Curr. Gastroenterol. Rep., 17, 21.

    Article  PubMed  PubMed Central  Google Scholar 

  177. Gomez-Gomez, G. J., Masedo, A., Yela, C., MartinezMontiel Mdel, P., and Casis, B. (2015) Current stage in inflammatory bowel disease: what is next? World J. Gastroenterol., 21, 11282–11303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Molecular Biology, Russian Academy of Sciences, 119991, Moscow, Russia

    E. O. Gubernatorova & A. V. Tumanov

  2. Department of Microbiology, Immunology, and Molecular Genetics, University of Texas Health Science Center, San Antonio, TX, 78229, USA

    A. V. Tumanov

Authors
  1. E. O. Gubernatorova
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. V. Tumanov
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A. V. Tumanov.

Additional information

Original Russian Text © E. О. Gubernatorova, A. V. Tumanov, 2016, published in Biokhimiya, 2016, Vol. 81, No. 11, pp. 1559–1577.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gubernatorova, E.O., Tumanov, A.V. Tumor necrosis factor and lymphotoxin in regulation of intestinal inflammation. Biochemistry Moscow 81, 1309–1325 (2016). https://doi.org/10.1134/S0006297916110092

Download citation

  • Received:

  • Revised:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S0006297916110092

Keywords

Search

Navigation