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Inflammatory Bowel Disease and Cytokine

염증성 장질환과 사이토카인

  • Choi, Eun Young (Department of Biological Science, Silla University) ;
  • Cho, Kwang Keun (Department of Animal Resources Technology, Gyeongnam National University of Science and Technology) ;
  • Choi, In Soon (Department of Biological Science, Silla University)
  • Received : 2013.03.13
  • Accepted : 2013.03.25
  • Published : 2013.03.30

Abstract

Inflammatory bowel disease, known as Crohn's disease and ulcerative colitis, is an unexplained disease characterized by chronic inflammation that repeats a cycle of relapse, improvement, and complications. The cause of inflammatory bowel disease is not clearly known, but it is predicted that a complex of various factors precipitate its occurrence. In particular, inflammatory mediators, such as cytokine, induce an increase in cell-mediated inflammatory responses. Focal tissue damage then occurs in the intestinal mucosa because of the weakening of the immune-modulating functions of cotton. Immune and inflammatory responses do not decrease appropriately but continue until they lead to chronic inflammation. Current research has focused on the cytokine genes, which have important roles in these inflammatory responses. Cytokine is a glycoprotein that is produced mostly in activated immune cells. It connects the activation, multiplication, and differentiation between immune cells, which causes focal tissue damage and inflammatory response. Moreover, butyrate, which originates in dietary fiber and plays an important role in the structure and function of the intestinal area, shows control functions in the intestinal immune system by decreasing the proinflammatory cytokine and increasing the anti-inflammatory cytokine. Therefore, this research investigated the molecular mechanism of the anti-inflammatory effects of butyrate to comprehend the cytokine controlling abilities of butyrate in the immune cells. Butyrate is expected to have potential in new treatment strategies for inflammatory bowel disease.

크론병과 궤양성 대장염으로 잘 알려져 있는 염증성 장질환은 재발과 호전을 반복하는 만성적인 염증 및 이에 따른 합병증을 특징으로 하는 원인 불명의 질환이다. 염증성 장질환의 발생 원인은 아직 명확히 알려져 있지 않지만 흡연이나 식이와 같은 환경적 요인, 장내 세균총과 같은 미생물학적 요인, 면역 매개에 의한 조직 손상과 같은 면역학적 요인 그리고 유전학적 요인 등이 복합적으로 발생기전에 관여 할 것이라고 추정한다. 특히 사이토카인과 같은 염증매개물질에 의해 세포매개염증반응의 일련의 과정이 유발 혹은 증폭되거나, 면역 조절 기능의 면화로 장 점막의 국소적 조직 손상을 유발하게 되며 면역 및 염증 반응이 적절하게 감소되지 않고 지속되어 만성 염증에 이르게 된다. 최근 이러한 염증반응에 중요한 역할을 담당하는 사이토카인 유전자에 관심이 몰리고 있다. 사이토카인은 활성화된 면역세포에서 주로 생성되는 당단백으로서 분자량이 8~10 kD 정도이며, 면역 반응시 T세포, B세포, 대식세포 등의 면역세포 상호간에 활성화, 증식 및 분화 등에 관계하여 국소적 조직 손상 및 염증반응을 일으킨다. 반면에 장의 구조와 기능에 있어 중요한 기질인 식이 섬유소에서 유래되는 Butyrate는 친염증성 사이토카인을 감소시키고 항염증성 사이토카인을 증가시킴으로써 장관 면역계에 대한 조절기능을 보이고 있다. 따라서 본 총설에서는 Butyrate의 항염증 효과에 대한 분자적 기작을 면역세포에서 Butyrate가 가지는 사이토카인 조절 능력을 통해 이해하고 Butyrate가 염증성 장질환에 대해 새로운 치료 전략을 제시 해 줄 것으로 기대한다.

Keywords

Acknowledgement

Supported by : National Research Foundation of Korea (NRF), Ministry Knowledge Economy

References

  1. Abraham, C. and Cho, J. 2009. Interleukin-23/Th17 pathways and inflammatory bowel disease. Inflamm Bowel Dis 15, 1090-1100. https://doi.org/10.1002/ibd.20894
  2. Alex, P., Zachos, N. C., Nguyen, T., Gonzales, L., Chen, T. E., Conklin, L. S., Centola, M. and Li, X. 2009. Distinct cytokine patterns identified from multiplex profiles of murine DSS and TNBS-induced colitis. Inflamm Bowel Dis 15, 341-352. https://doi.org/10.1002/ibd.20753
  3. Brand, S. 2009. Crohn's disease: Th1, Th17 or both? The change of a paradigm: new immunological and genetic insights implicate Th17 cells in the pathogenesis of Crohn's disease. Gut 58, 1152-1167. https://doi.org/10.1136/gut.2008.163667
  4. Camoglio, L., Te Velde, A. A., Tigges, A. J., Das, P. K. and Van Deventer, S. J. 1998. Altered expression of interferon- gamma and interleukin-4 in inflammatory bowel disease. Inflamm Bowel Dis 4, 285-290.
  5. Castrilli, G., Tatone, D., Diodoro, M. G., Rosini, S., Piantelli, M. and Musiani, P. 1997. Interleukin 1alpha and interleukin 6 promote the in vitro growth of both normal and neoplastic human cervical epithelial cells. Br J Cancer 75, 855-859. https://doi.org/10.1038/bjc.1997.152
  6. Ceciliani, F., Giordano, A. and Spagnolo, V. 2002. The systemic reaction during inflammation: the acute-phase proteins. Protein Pept Lett 9, 211-223. https://doi.org/10.2174/0929866023408779
  7. Chakravortty, D., Koide, N., Kato, Y., Sugiyama, T., Mu, M. M., Yoshida, T. and Yokochi, T. 2000. The inhibitory action of butyrate on lipopolysaccharide-induced nitric oxide production in RAW 264.7 murine macrophage cells. J Endotoxin Res 6, 243-247. https://doi.org/10.1177/09680519000060030501
  8. Chen, P. S., Wang, C. C., Bortner, C. D., Peng, G. S., Wu, X., Pang, H., Lu, R. B., Gean, P. W., Chuang, D. M. and Hong, J. S. 2007. Valproic acid and other histone deacetylase inhibitors induce microglial apoptosis and attenuate lipopolysaccharide- induced dopaminergic neurotoxicity. Neuroscience 149, 203-212. https://doi.org/10.1016/j.neuroscience.2007.06.053
  9. Cho, M. S., Song, S. M., Oh, S. H., Lee, Y. J. Jang, J. Y. and Kim, K. M. 2011. Tumor necrosis factor-${\alpha}$ gene polymorphisms in Korean children with inflammatory bowel disease. Korean J Pediatr Gastroenterol Nutr 14, 269-278. https://doi.org/10.5223/kjpgn.2011.14.3.269
  10. Cummings, J. H. 1983. Fermentation in the human large intestine: evidence and implications for health. Lancet 1, 1206-1209.
  11. D'Haens, G., Van Deventer, S., Van Hogezand, R., Chalmers, D., Kothe, C., Baert, F., Braakman, T., Schaible, T., Geboes, K. and Rutgeerts, P. 1999. Endoscopic and histological healing with infliximab anti-tumor necrosis factor antibodies in Crohn's disease: A European multicenter trial. Gastroenterology 116, 1029-1034. https://doi.org/10.1016/S0016-5085(99)70005-3
  12. Dijkstra, G., Moshage, H. and Jansen, P. L. 2002. Blockade of NF-kappaB activation and donation of nitric oxide: new treatment options in inflammatory bowel disease? Scand J Gastroenterol Suppl 236, 37-41.
  13. Dionne, S., Hiscott, J., D'Agata, I., Duhaime, A. and Seidman, E. G. 1997. Quantitative PCR analysis of TNF-alpha and IL-1 beta mRNA levels in pediatric IBD mucosal biopsies. Dig Dis Sci 42, 1557-1566. https://doi.org/10.1023/A:1018895500721
  14. Di Sabatino, A., Morera, R., Ciccocioppo, R., Cazzola, P., Gotti, S., Tinozzi, F. P., Tinozzi, S. and Corazza, G. R. 2005. Oral butyrate for mildly to moderately active Crohn's disease. Aliment Pharmacol Ther 22, 789-794. https://doi.org/10.1111/j.1365-2036.2005.02639.x
  15. Duerr, R. H., Taylor, K. D., Brant, S. R., Rioux, J. D., Silverberg, M. S., Daly, M. J., Steinhart, A. H., Abraham, C., Regueiro, M., Griffiths, A., Dassopoulos, T., Bitton, A., Yang, H., Targan, S., Datta, L. W., Kistner, E. O., Schumm, L. P., Lee, A. T., Gregersen, P. K., Barmada, M. M., Rotter, J. I., Nicolae, D. L. and Cho, J. H. 2006. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314, 1461-1463. https://doi.org/10.1126/science.1135245
  16. Fedorak, R. N., Gangl, A., Elson, C. O., Rutgeerts, P., Schreiber, S., Wild, G., Hanauer, S. B., Kilian, A., Cohard, M., LeBeaut, A. and Feagan, B. 2000. Recombinant human interleukin 10 in the treatment of patients with mild to moderately active Crohn's disease. The Interleukin 10 Inflammatory Bowel Disease Cooperative Study Group. Gastroenterology 119, 1473-1482. https://doi.org/10.1053/gast.2000.20229
  17. Fukae, J., Amasaki, Y., Yamashita, Y., Bohgaki, T., Yasuda, S., Jodo, S., Atsumi, T. and Koike, T. 2005. Butyrate suppresses tumor necrosis factor alpha production by regulating specific messenger RNA degradation mediated through a cis-acting AU-rich element. Arthritis Rheum 52, 2697-2707. https://doi.org/10.1002/art.21258
  18. Goustin, A. S., Leof, E. B., Shipley, G. D. and Moses, H. L. 1986. Growth factors and cancer. Cancer Res 46, 1015-1029.
  19. Goyette, P., Labbe, C., Trinh, T. T., Xavier, R. J. and Rioux, J. D. 2007. Molecular pathogenesis of inflammatory bowel disease: genotypes, phenotypes and personalized medicine. Ann Med 39, 177-199. https://doi.org/10.1080/07853890701197615
  20. Hamer, H. M., Jonkers, D., Venema, K., Vanhoutvin, S., Troost, F. J. and Brummer, R. J. 2008. Review article: the role of butyrate on colonic function. Aliment Pharmacol Ther 27, 104-119.
  21. Hanai, H., Takeda, Y., Eberhardson, M., Gruber, R., Saniabadi, A. R., Winqvist, O. and Lofberg, R. 2011. The mode of actions of the Adacolumn therapeutic leucocytapheresis in patients with inflammatory bowel disease: a concise review. Clin Exp Immunol 163, 50-58. https://doi.org/10.1111/j.1365-2249.2010.04279.x
  22. Harrington, L. E., Hatton, R. D., Mangan, P. R., Turner, H., Murphy, T. L., Murphy, K. M. and Weaver, C. T. 2005. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol 6, 1123-1132. https://doi.org/10.1038/ni1254
  23. Herfarth, H. H., Mohanty, S. P., Rath, H. C., Tonkonogy, S. and Sartor, R. B. 1996. Interleukin 10 suppresses experimental chronic, granulomatous inflammation induced by bacterial cell wall polymers. Gut 39, 836-845. https://doi.org/10.1136/gut.39.6.836
  24. Hommes, D. W., Mikhajlova, T. L., Stoinov, S., Stimac, D., Vucelic, B., Lonovics, J., Zakuciova, M., D'Haens, G., Van Assche, G., Ba, S., Lee, S. and Pearce, T. 2006. Fontolizumab, a humanised anti-interferon gamma antibody, demonstrates safety and clinical activity in patients with moderate to severe Crohn's disease. Gut 55, 1131-1137.
  25. Huuskonen, J., Suuronen, T., Nuutinen, T., Kyrylenko, S. and Salminen, A. 2004. Regulation of microglial inflammatory response by sodium butyrate and short-chain fatty acids. Br J Pharmacol 141, 874-880. https://doi.org/10.1038/sj.bjp.0705682
  26. Izcue, A., Coombes, J. L. and Powrie, F. 2009. Regulatory lymphocytes and intestinal inflammation. Annu Rev Immunol 27, 313-338. https://doi.org/10.1146/annurev.immunol.021908.132657
  27. Jang, B. I. 2007. Clinical Update: Inflammatory bowel disease. Yeungnam Uni J Med 24, S221-233.
  28. Jeon, C. H., Kim, J. H., Park, J. H., Ahn, K. S., Kim, H. J., Kim, E. H., Ahn, J. K., Cha, H. S. and Koh, E. M. 2003. Cytokine profiles in synovial fluid of rheumatoid arthritis. Korean J Med 64, 576-587.
  29. Jung, W. T., Shin, W. C., Choi, W. C., Lee, J. H. and Kim, K. Y. 1999. Chemokine Gene Expression in the Colonic Mucosa of Patients with Ulcerative Colitis and Crohn's Disease - Analysis by Quantitative reverse Transcriptional polymerase Chain Reaction using synthetic Standard RNA. Inje Med J 20, 257-269.
  30. Kanneganti, T. D., Lamkanfi, M. and Nunez, G. 2007. Intracellular NOD-like receptors in host defense and disease. Immunity 27, 549-559. https://doi.org/10.1016/j.immuni.2007.10.002
  31. Kaser, A., Zeissig, S. and Blumberg, R. S. 2010. Inflammatory bowel disease. Annu Rev Immunol 28, 573-621. https://doi.org/10.1146/annurev-immunol-030409-101225
  32. Kim, B. J., Song, S. M., Kim, K. M., Lee, Y. J., Rhee, K. W., Jang, J. Y., Park, S. J. and Yoon, C. H. 2010. Characteristics and trends in the incidence of inflammatory bowel disease in Korean children: a single-center experience. Dig Dis Sci 55, 1989-1995. https://doi.org/10.1007/s10620-009-0963-5
  33. Kim, J. M. 2010. Inflammatory bowel diseases and enteric microbiota. Korean J Gastroenterol 55, 4-18. https://doi.org/10.4166/kjg.2010.55.1.4
  34. Kim, J. M. 2011. Inflammatory bowel diseases and inflammasome. Korean J Gastroenterol 58, 300-310. https://doi.org/10.4166/kjg.2011.58.6.300
  35. Kim, K. H. 2009. Effects of chitosan on the production of Th1 and Th2 cytokines in mice. J Life Sci 19, 411-416. https://doi.org/10.5352/JLS.2009.19.3.411
  36. Kim, T. H., Kim, B. G., Shin, H. D., Kim, J. W., Kim, C. G., Kim, J. S., Jung, H. C. and Song, I. S. 2003. Tumor necrosis factor-${\alpha}$ and Interleukin-10 gene polymorphisms in Korean patients with inflammatory bowel disease. Korean J Gastroenterol 42, 377-386.
  37. Kinoshita, M., Suzuki, Y. and Saito, Y. 2002. Butyrate reduces colonic paracellular permeability by enhancing PPARgamma activation. Biochem Biophys Res Commun 293, 827-831. https://doi.org/10.1016/S0006-291X(02)00294-2
  38. Kirschner, B. S. 1998. Safety of azathioprine and 6-mercaptopurine in pediatric patients with inflammatory bowel disease. Gastroenterology 115, 813-821. https://doi.org/10.1016/S0016-5085(98)70251-3
  39. Klagsbrun, M. and D'Amore, P. A. 1991. Regulators of angiogenesis. Annu Rev Physiol 53, 217-239. https://doi.org/10.1146/annurev.ph.53.030191.001245
  40. Kleessen, B., Kroesen, A. J., Buhr, H. J. and Blaut, M. 2002. Mucosal and invading bacteria in patients with inflammatory bowel disease compared with controls. Scand J Gastroenterol 37, 1034-1041. https://doi.org/10.1080/003655202320378220
  41. Kobayashi, T., Okamoto, S., Hisamatsu, T., Kamada, N., Chinen, H., Saito, R., Kitazume, M. T., Nakazawa, A., Sugita, A., Koganei, K., Isobe, K. and Hibi, T. 2008. IL23 differentially regulates the Th1/Th17 balance in ulcerative colitis and Crohn's disease. Gut 57, 1682-1689. https://doi.org/10.1136/gut.2007.135053
  42. Koenders, M. I. and van den Berg, W. B. 2010. Translational mini-review series on Th17 cells: are T helper 17 cells really pathogenic in autoimmunity? Clin Exp Immunol 159, 131-136. https://doi.org/10.1111/j.1365-2249.2009.04039.x
  43. Koloski, N. A., Bret, L. and Radford-Smith, G. 2008. Hygiene hypothesis in inflammatory bowel disease: a critical review of the literature. World J Gastroenterol 14, 165-173. https://doi.org/10.3748/wjg.14.165
  44. Kuhn, R., Lohler, J., Rennick, D., Rajewsky, K. and Muller, W. 1993. Interleukin-10-deficient mice develop chronic enterocolitis. Cell 75, 263-274. https://doi.org/10.1016/0092-8674(93)80068-P
  45. Lee, K. L., Kim, C. G., Kim, B. G., Chang, D. K., Lee, D. H., Kim, J. S., Jung, H. C. Lee, Y., Park, J. S. and Song, I. S. 2003. Down-regulatory effect of Interleukin-10 gene transfection for CXC chemokines in colonic epithelial cell. Korean J Gastroenterol 41, 447-455.
  46. Lewis, C. M., Whitwell, S. C., Forbes, A., Sanderson, J., Mathew, C. G. and Marteau, T. M. 2007. Estimating risks of common complex diseases across genetic and environmental factors: the example of Crohn disease. J Med Genet 44, 689-694. https://doi.org/10.1136/jmg.2007.051672
  47. Liu, L., Li, L., Min, J., Wang, J., Wu, H., Zeng, Y., Chen, S. and Chu, Z. 2012. Butyrate interferes with the differentiation and function of human monocyte-derived dendritic cells. Cell Immunol 277, 66-73. https://doi.org/10.1016/j.cellimm.2012.05.011
  48. MacDermott, R. P. and Stenson, W. F. 1988. Alterations of the immune system in ulcerative colitis and Crohn's disease. Adv Immunol 42, 285-328. https://doi.org/10.1016/S0065-2776(08)60848-2
  49. Mangan, P. R., Harrington, L. E., O'Quinn, D. B., Helms, W. S., Bullard, D. C., Elson, C. O., Hatton, R. D., Wahl, S. M., Schoeb, T. R. and Weaver, C. T. 2006. Transforming growth factor-beta induces development of the T(H)17 lineage. Nature 441, 231-234. https://doi.org/10.1038/nature04754
  50. Mosmann, T. R. and Sad, S. 1996. The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol Today 17, 138-146. https://doi.org/10.1016/0167-5699(96)80606-2
  51. Neurath, M. F. 2007. IL-23: a master regulator in Crohn disease. Nat Med 13, 26-28. https://doi.org/10.1038/nm0107-26
  52. O'Connor, W., Jr., Kamanaka, M., Booth, C. J., Town, T., Nakae, S., Iwakura, Y., Kolls, J. K. and Flavell, R. A. 2009. A protective function for interleukin 17A in T cell-mediated intestinal inflammation. Nat Immunol 10, 603-609. https://doi.org/10.1038/ni.1736
  53. Pacheco, R. G., Esposito, C. C., Muller, L. C., Castelo-Branco, M. T., Quintella, L. P., Chagas, V. L., de Souza, H. S. and Schanaider, A. 2012. Use of butyrate or glutamine in enema solution reduces inflammation and fibrosis in experimental diversion colitis. World J Gastroenterol 18, 4278-4287. https://doi.org/10.3748/wjg.v18.i32.4278
  54. Park, J. S., Lee, E. J., Lee, J. C., Kim, W. K. and Kim, H. S. 2007. Anti-inflammatory effects of short chain fatty acids in IFN-gamma-stimulated RAW 264.7 murine macrophage cells: involvement of NF-kappaB and ERK signaling pathways. Int Immunopharmacol 7, 70-77. https://doi.org/10.1016/j.intimp.2006.08.015
  55. Pender, S. L., Breese, E. J., Gunther, U., Howie, D., Wathen, N. C., Schuppan, D. and MacDonald, T. T. 1998. Suppression of T cell-mediated injury in human gut by interleukin 10: role of matrix metalloproteinases. Gastroenterology 115, 573-583. https://doi.org/10.1016/S0016-5085(98)70136-2
  56. Perez, R., Stevenson, F., Johnson, J., Morgan, M., Erickson, K., Hubbard, N. E., Morand, L., Rudich, S., Katznelson, S. and German, J. B. 1998. Sodium butyrate upregulates Kupffer cell PGE2 production and modulates immune function. J Surg Res 78, 1-6. https://doi.org/10.1006/jsre.1998.5316
  57. Powrie, F., Leach, M. W., Mauze, S., Menon, S., Caddle, L. B. and Coffman, R. L. 1994. Inhibition of Th1 responses prevents inflammatory bowel disease in scid mice reconstituted with CD45RBhi CD4+ T cells. Immunity 1, 553-562. https://doi.org/10.1016/1074-7613(94)90045-0
  58. Reif, S., Klein, I., Lubin, F., Farbstein, M., Hallak, A. and Gilat, T. 1997. Pre-illness dietary factors in inflammatory bowel disease. Gut 40, 754-760. https://doi.org/10.1136/gut.40.6.754
  59. Reinisch, W., de Villiers, W., Bene, L., Simon, L., Racz, I., Katz, S., Altorjay, I., Feagan, B., Riff, D., Bernstein, C. N., Hommes, D., Rutgeerts, P., Cortot, A., Gaspari, M., Cheng, M., Pearce, T. and Sands, B. E. 2010. Fontolizumab in moderate to severe Crohn's disease: a phase 2, randomized, double- blind, placebo-controlled, multiple-dose study. Inflamm Bowel Dis 16, 233-242. https://doi.org/10.1002/ibd.21038
  60. Roediger, W. E. 1980. Role of anaerobic bacteria in the metabolic welfare of the colonic mucosa in man. Gut 21, 793-798. https://doi.org/10.1136/gut.21.9.793
  61. Roediger, W. E. 1982. Utilization of nutrients by isolated epithelial cells of the rat colon. Gastroenterology 83, 424-429.
  62. Rogy, M. A., Beinhauer, B. G., Reinisch, W., Huang, L. and Pokieser, P. 2000. Transfer of interleukin-4 and interleukin- 10 in patients with severe inflammatory bowel disease of the rectum. Hum Gene Ther 11, 1731-1741. https://doi.org/10.1089/10430340050111386
  63. Saemann, M. D., Bohmig, G. A., Osterreicher, C. H., Burtscher, H., Parolini, O., Diakos, C., Stockl, J., Horl, W. H. and Zlabinger, G. J. 2000. Anti-inflammatory effects of sodium butyrate on human monocytes: potent inhibition of IL-12 and up-regulation of IL-10 production. FASEB J 14, 2380-2382.
  64. Sandborn, W. J. and Targan, S. R. 2002. Biologic therapy of inflammatory bowel disease. Gastroenterology 122, 1592-1608. https://doi.org/10.1053/gast.2002.33426
  65. Sandborn, W. J., Feagan, B. G., Fedorak, R. N., Scherl, E., Fleisher, M. R., Katz, S., Johanns, J., Blank, M., Rutgeerts, P. and Ustekinumab Crohn's Disease Study, G. 2008. A randomized trial of Ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with moderate-to-severe Crohn's disease. Gastroenterology 135, 1130-1141. https://doi.org/10.1053/j.gastro.2008.07.014
  66. Sands, B. E. 1997. Biologic therapy for inflammatory bowel disease. Inflamm Bowel Dis 3, 95-113.
  67. Sartor, R. B. 1991. Pathogenetic and clinical relevance of cytokines in inflammatory bowel disease. Immunol Res 10, 465-471. https://doi.org/10.1007/BF02919743
  68. Sartor, R. B. 1994. Cytokines in intestinal inflammation: pathophysiological and clinical considerations. Gastroenterology 106, 533-539.
  69. Sashio, H., Tamura, K., Ito, R., Yamamoto, Y., Bamba, H., Kosaka, T., Fukui, S., Sawada, K., Fukuda, Y., Tamura, K., Satomi, M., Shimoyama, T. and Furuyama, J. 2002. Polymorphisms of the TNF gene and the TNF receptor superfamily member 1B gene are associated with susceptibility to ulcerative colitis and Crohn's disease, respectively. Immunogenetics 53, 1020-1027. https://doi.org/10.1007/s00251-001-0423-7
  70. Scheppach, W. and Weiler, F. 2004. The butyrate story: old wine in new bottles? Curr Opin Clin Nutr Metab Care 7, 563-567. https://doi.org/10.1097/00075197-200409000-00009
  71. Schreiber, S., Fedorak, R. N., Nielsen, O. H., Wild, G., Williams, C. N., Nikolaus, S., Jacyna, M., Lashner, B. A., Gangl, A., Rutgeerts, P., Isaacs, K., van Deventer, S. J., Koningsberger, J. C., Cohard, M., LeBeaut, A. and Hanauer, S. B. 2000. Safety and efficacy of recombinant human interleukin 10 in chronic active Crohn's disease. Crohn's Disease IL-10 Cooperative Study Group. Gastroenterology 119, 1461-1472. https://doi.org/10.1053/gast.2000.20196
  72. Segain, J. P., Raingeard de la Bletiere, D., Bourreille, A., Leray, V., Gervois, N., Rosales, C., Ferrier, L., Bonnet, C., Blottiere, H. M. and Galmiche, J. P. 2000. Butyrate inhibits inflammatory responses through NFkappaB inhibition: implications for Crohn's disease. Gut 47, 397-403. https://doi.org/10.1136/gut.47.3.397
  73. Siegmund, B. 2002. Interleukin-1beta converting enzyme (caspase-1) in intestinal inflammation. Biochem Pharmacol 64, 1-8. https://doi.org/10.1016/S0006-2952(02)01064-X
  74. Soderholm, J. D., Streutker, C., Yang, P. C., Paterson, C., Singh, P. K., McKay, D. M., Sherman, P. M., Croitoru, K. and Perdue, M. H. 2004. Increased epithelial uptake of protein antigens in the ileum of Crohn's disease mediated by tumour necrosis factor alpha. Gut 53, 1817-1824. https://doi.org/10.1136/gut.2004.041426
  75. Targan, S. R., Hanauer, S. B., van Deventer, S. J., Mayer, L., Present, D. H., Braakman, T., DeWoody, K. L., Schaible, T. F. and Rutgeerts, P. J. 1997. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn's disease. Crohn's Disease cA2 Study Group. N Engl J Med 337, 1029-1035. https://doi.org/10.1056/NEJM199710093371502
  76. Tilg, H., Moschen, A. R., Kaser, A., Pines, A. and Dotan, I. 2008. Gut, inflammation and osteoporosis: basic and clinical concepts. Gut 57, 684-694. https://doi.org/10.1136/gut.2006.117382
  77. Tysk, C., Lindberg, E., Jarnerot, G. and Floderus-Myrhed, B. 1988. Ulcerative colitis and Crohn's disease in an unselected population of monozygotic and dizygotic twins. A study of heritability and the influence of smoking. Gut 29, 990-996. https://doi.org/10.1136/gut.29.7.990
  78. Usami, M., Kishimoto, K., Ohata, A., Miyoshi, M., Aoyama, M., Fueda, Y. and Kotani, J. 2008. Butyrate and trichostatin A attenuate nuclear factor kappaB activation and tumor necrosis factor alpha secretion and increase prostaglandin E2 secretion in human peripheral blood mononuclear cells. Nutr Res 28, 321-328. https://doi.org/10.1016/j.nutres.2008.02.012
  79. van Deventer, S. J., Elson, C. O. and Fedorak, R. N. 1997. Multiple doses of intravenous interleukin 10 in steroidrefractory Crohn's disease. Crohn's Disease Study Group. Gastroenterology 113, 383-389. https://doi.org/10.1053/gast.1997.v113.pm9247454
  80. van Driel, W. J., Kievit-Tyson, P., van den Broek, L. C., Zwinderman, A. H., Trimbos, B. J. and Fleuren, G. J. 1999. Presence of an eosinophilic infiltrate in cervical squamous carcinoma results from a type 2 immune response. Gynecol Oncol 74, 188-195. https://doi.org/10.1006/gyno.1999.5431
  81. van Dullemen, H. M., van Deventer, S. J., Hommes, D. W., Bijl, H. A., Jansen, J., Tytgat, G. N. and Woody, J. 1995. Treatment of Crohn's disease with anti-tumor necrosis factor chimeric monoclonal antibody (cA2). Gastroenterology 109, 129-135. https://doi.org/10.1016/0016-5085(95)90277-5
  82. Vinolo, M. A., Rodrigues, H. G., Nachbar, R. T. and Curi, R. 2011. Regulation of inflammation by short chain fatty acids. Nutrients 3, 858-876. https://doi.org/10.3390/nu3100858
  83. Werts, C., Rubino, S., Ling, A., Girardin, S. E. and Philpott, D. J. 2011. Nod-like receptors in intestinal homeostasis, inflammation, and cancer. J Leukoc Biol 90, 471-482. https://doi.org/10.1189/jlb.0411183