Master regulator of intestinal disease: IL-6 in chronic inflammation and cancer development

Seminars in Immunology

Volumn 26, Issue 1, 2014, Pages 75-79

  Waldner, Maximilian J ^a   Neurath, Markus F ^a  

^a UNIVERSITY OF ERLANGEN NUREMBERG   (Germany)

Author keywords

Colorectal cancer; Crohn's disease; Cytokines; Inflammatory bowel disease; Interleukin 6; JAK; SOCS3; STAT3; Ulcerative colitis

Indexed keywords

INTERLEUKIN 6; SILTUXIMAB; STAT3 PROTEIN; TOCILIZUMAB;

CARCINOGENESIS; CELL DIFFERENTIATION; CELL PROLIFERATION; CELL SURVIVAL; CHRONIC INFLAMMATION; COLORECTAL CANCER; CROHN DISEASE; CYTOKINE RELEASE; ENTEROPATHY; HUMAN; INFLAMMATORY BOWEL DISEASE; MACROPHAGE; NONHUMAN; PATHOGENESIS; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN TARGETING; REVIEW; SIGNAL TRANSDUCTION; T LYMPHOCYTE; T LYMPHOCYTE ACTIVATION; TUMOR CELL; TUMOR GROWTH; ULCERATIVE COLITIS;

COLORECTAL CANCER; CROHN'S DISEASE; CYTOKINES; INFLAMMATORY BOWEL DISEASE; INTERLEUKIN-6; JAK; SOCS3; STAT3; ULCERATIVE COLITIS;

ANIMALS; CELL TRANSFORMATION, NEOPLASTIC; COLORECTAL NEOPLASMS; GENE EXPRESSION REGULATION; HUMANS; INFLAMMATORY BOWEL DISEASES; INTERLEUKIN-6; MOLECULAR TARGETED THERAPY; SIGNAL TRANSDUCTION; STAT3 TRANSCRIPTION FACTOR; T-LYMPHOCYTE SUBSETS;

EID: 84896495700     PISSN: 10445323     EISSN: 10963618     Source Type: Journal    
DOI: 10.1016/j.smim.2013.12.003     Document Type: Review

References (70)

1. Podolsky D.K. Inflammatory bowel disease. N Engl J Med 2002, 347:417-429.
2. Baumgart D.C., Sandborn W.J. Inflammatory bowel disease: clinical aspects and established and evolving therapies. Lancet 2007, 369:1641-1657.
3. Nikolaus S., Schreiber S. Diagnostics of inflammatory bowel disease. Gastroenterology 2007, 133:1670-1689.
4. Neumann H., Neurath M.F., Mudter J. New endoscopic approaches in IBD. World J Gastroenterol 2011, 17:63-68.
5. Isaacs K.L., Lewis J.D., Sandborn W.J., Sands B.E., Targan S.R. State of the art: IBD therapy and clinical trials in IBD. Inflamm Bowel Dis 2005, 11(Suppl. 1):S3-S12.
6. Sartor R.B. Mechanisms of disease: pathogenesis of Crohn's disease and ulcerative colitis. Nat Clin Pract Gastroenterol Hepatol 2006, 3:390-407.
7. Kaser A., Zeissig S., Blumberg R.S. Inflammatory bowel disease. Annu Rev Immunol 2010, 28:573-621.
8. Atreya R., Neurath M.F. New therapeutic strategies for treatment of inflammatory bowel disease. Mucosal Immunol 2008, 1:175-182.
9. Hirano T. Interleukin 6 and its receptor: ten years later. Int Rev Immunol 1998, 16:249-284.
10. Diehl S., Rincon M. The two faces of IL-6 on Th1/Th2 differentiation. Mol Immunol 2002, 39:531-536.
11. Kishimoto T., Akira S., Taga T. Interleukin-6 and its receptor: a paradigm for cytokines. Science (New York, NY) 1992, 258:593-597.
12. Naugler W.E., Karin M. The wolf in sheep's clothing: the role of interleukin-6 in immunity, inflammation and cancer. Trends Mol Med 2008, 14:109-119.
13. Scheller J., Ohnesorge N., Rose-John S. Interleukin-6 trans-signalling in chronic inflammation and cancer. Scand J Immunol 2006, 63:321-329.
14. Rose-John S., Neurath M.F. IL-6 trans-signaling: the heat is on. Immunity 2004, 20:2-4.
15. Schuster B., Kovaleva M., Sun Y., Regenhard P., Matthews V., Grötzinger J., et al. Signaling of human ciliary neurotrophic factor (CNTF) revisited, the interleukin-6 receptor can serve as an alpha-receptor for CTNF. J Biol Chem 2003, 278:9528-9535.
16. Crabé S., Guay-Giroux A., Tormo A.J., Duluc D., Lissilaa R., Guilhot F., et al. The IL-27 p28 subunit binds cytokine-like factor 1 to form a cytokine regulating NK and T cell activities requiring IL-6R for signaling. J Immunol 2009, 183:7692-7702.
17. Tormo A.J., Meliani Y., Beaupré L.A., Sharma M., Fritz J.H., Elson G., et al. The composite cytokine p28/cytokine-like factor 1 sustains B cell proliferation and promotes plasma cell differentiation. J Immunol 2013, 191:1657-1665.
18. Garbers C., Spudy B., Aparicio-Siegmund S., Waetzig G.H., Sommer J., Hölscher C., et al. An interleukin-6 receptor-dependent molecular switch mediates signal transduction of the IL-27 cytokine subunit p28 (IL-30) via a gp130 protein receptor homodimer. J Biol Chem 2013, 288:4346-4354.
19. Mitsuyama K., Sata M., Rose-John S. Interleukin-6 trans-signaling in inflammatory bowel disease. Cytokine Growth Factor Rev 2006, 17:451-461.
20. Jones G.W., McLoughlin R.M., Hammond V.J., Parker C.R., Williams J.D., Malhotra R., et al. Loss of CD4+ T Cell IL-6R expression during inflammation underlines a role for IL-6 trans signaling in the local maintenance of Th17 cells. J Immunol 2010, 184:2130-2139.
21. Bluyssen H.A.R., Rastmanesh M.M., Tilburgs C., Jie K., Wesseling S., Goumans M.-J., et al. IFN gamma-dependent SOCS3 expression inhibits IL-6-induced STAT3 phosphorylation and differentially affects IL-6 mediated transcriptional responses in endothelial cells. Am J Physiol Cell Physiol 2010, 299:C354-C362.
22. Gross V., Andus T., Caesar I., Roth M., Schölmerich J. Evidence for continuous stimulation of interleukin-6 production in Crohn's disease. Gastroenterology 1992, 102:514-519.
23. Hyams J.S., Fitzgerald J.E., Treem W.R., Wyzga N., Kreutzer D.L. Relationship of functional and antigenic interleukin 6 to disease activity in inflammatory bowel disease. Gastroenterology 1993, 104:1285-1292.
24. Louis E., Belaiche J., van Kemseke C., Franchimont D., de Groote D., Gueenen V., et al. A high serum concentration of interleukin-6 is predictive of relapse in quiescent Crohn's disease. Eur J Gastroenterol Hepatol 1997, 9:939-944.
25. Van Kemseke C., Belaiche J., Louis E. Frequently relapsing Crohn's disease is characterized by persistent elevation in interleukin-6 and soluble interleukin-2 receptor serum levels during remission. Int J Colorectal Dis 2000, 15:206-210.
26. Groblewska M., Mroczko B., Wereszczyńska-Siemiatkowska U., Kedra B., Lukaszewicz M., Baniukiewicz A., et al. Serum interleukin 6 (IL-6) and C-reactive protein (CRP) levels in colorectal adenoma and cancer patients. Clin Chem Lab Med 2008, 46:1423-1428.
27. Suzuki Y., Saito H., Kasanuki J., Kishimoto T., Tamura Y., Yoshida S. Significant increase of interleukin 6 production in blood mononuclear leukocytes obtained from patients with active inflammatory bowel disease. Life Sci 1990, 47:2193-2197.
28. Reinecker H.C., Steffen M., Witthoeft T., Pflueger I., Schreiber S., MacDermott R.P., et al. Enhanced secretion of tumour necrosis factor-alpha, IL-6, and IL-1 beta by isolated lamina propria mononuclear cells from patients with ulcerative colitis and Crohn's disease. Clin Exp Immunol 1993, 94:174-181.
29. Kusugami K., Fukatsu A., Tanimoto M., Shinoda M., Haruta J., Kuroiwa A., et al. Elevation of interleukin-6 in inflammatory bowel disease is macrophage- and epithelial cell-dependent. Dig Dis Sci 1995, 40:949-959.
30. Hosokawa T., Kusugami K., Ina K., Ando T., Shinoda M., Imada A., et al. Interleukin-6 and soluble interleukin-6 receptor in the colonic mucosa of inflammatory bowel disease. J Gastroenterol Hepatol 1999, 14:987-996.
31. Fuss I.J., Neurath M.F., Boirivant M., Klein J.S., de La Motte C., Strong S.A., et al. Disparate CD4+ lamina propria (LP) lymphokine secretion profiles in inflammatory bowel disease, Crohn's disease LP cells manifest increased secretion of IFN-gamma, whereas ulcerative colitis LP cells manifest increased secretion of IL-5. J Immunol (Baltimore, Md 1950) 1996, 157:1261-1270.
32. Neurath M.F., Fuss I.J., Kelsall B.L., Presky D.H., Waegell W., Strober W. Experimental granulomatous colitis in mice is abrogated by induction of TGF-beta-mediated oral tolerance. J Exp Med 1996, 183:2605-2616.
33. Sarra M., Pallone F., MacDonald T.T., Monteleone G. IL-23/IL-17 axis in IBD. Inflamm Bowel Dis 2010, 16:1808-1813.
34. Rogler G., Andus T. Cytokines in inflammatory bowel disease. World J Surg 1998, 22:382-389.
35. Sanchez-Munoz F., Dominguez-Lopez A., Yamamoto-Furusho J.-K. Role of cytokines in inflammatory bowel disease. World J Gastroenterol 2008, 14:4280-4288.
36. Fichtner-Feigl S., Fuss I.J., Preiss J.C., Strober W., Kitani A. Treatment of murine Th1- and Th2-mediated inflammatory bowel disease with NF-kappa B decoy oligonucleotides. J Clin Invest 2005, 115:3057-3071.
37. Atreya R., Mudter J., Finotto S., Müllberg J., Jostock T., Wirtz S., et al. Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: evidence in Crohn disease and experimental colitis in vivo. Nat Med 2000, 6:583-588.
38. Yen D., Cheung J., Scheerens H., Poulet F., McClanahan T., McKenzie B., et al. IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J Clin Invest 2006, 116:1310-1316.
39. Yamamoto M., Yoshizaki K., Kishimoto T., Ito H. IL-6 is required for the development of Th1 cell-mediated murine colitis. J Immunol 2000, 164:4878-4882.
40. Kimura A., Kishimoto T. IL-6: regulator of Treg/Th17 balance. Eur J Immunol 2010, 40:1830-1835.
41. Leppkes M., Becker C., Ivanov I.I., Hirth S., Wirtz S., Neufert C., et al. RORγ-expressing Th17 cells induce murine chronic intestinal inflammation via redundant effects of IL-17A and IL-17F. Gastroenterology 2009, 136:257-267.
42. Mudter J., Neurath M.F. Il-6 signaling in inflammatory bowel disease: pathophysiological role and clinical relevance. Inflamm Bowel Dis 2007, 13:1016-1023.
43. Noguchi D., Wakita D., Tajima M., Ashino S., Iwakura Y., Zhang Y., et al. Blocking of IL-6 signaling pathway prevents CD4+ T cell-mediated colitis in a T(h)17-independent manner. Int Immunol 2007, 19:1431-1440.
44. Fujimoto M., Nakano M., Terabe F., Kawahata H., Ohkawara T., Han Y., et al. The influence of excessive IL-6 production in vivo on the development and function of Foxp3+ regulatory T cells. J Immunol 2011, 186:32-40.
45. Hokama A., Mizoguchi E., Sugimoto K., Shimomura Y., Tanaka Y., Yoshida M., et al. Induced reactivity of intestinal CD4(+) T cells with an epithelial cell lectin, galectin-4, contributes to exacerbation of intestinal inflammation. Immunity 2004, 20:681-693.
46. Weigmann B., Lehr H.A., Yancopoulos G., Valenzuela D., Murphy A., Stevens S., et al. The transcription factor NFATc2 controls IL-6-dependent T cell activation in experimental colitis. J Exp Med 2008, 205:2099-2110.
47. Mudter J., Amoussina L., Schenk M., Yu J., Brüstle A., Weigmann B., et al. The transcription factor IFN regulatory factor-4 controls experimental colitis in mice via T cell-derived IL-6. J Clin Invest 2008, 118:2415-2426.
48. Becker C., Fantini M.C. IL-6 signaling promotes tumor growth in colorectal cancer. Cell Cycle 2005, 4:220-223.
49. Lahm H., Petral-Malec D., Yilmaz-Ceyhan A., Fischer J.R., Lorenzoni M., Givel J.C., et al. Growth stimulation of a human colorectal carcinoma cell line by interleukin-1 and -6 and antagonistic effects of transforming growth factor beta 1. Eur J Cancer 1992, 28A:1894-1899.
50. Becker C., Fantini M.C., Schramm C., Lehr H.A., Wirtz S., Nikolaev A., et al. TGF-beta suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling. Immunity 2004, 21:491-501.
51. Grivennikov S., Karin E., Terzic J., Mucida D., Yu G.-Y., Vallabhapurapu S., et al. IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell 2009, 15:103-113.
52. Bollrath J., Phesse T.J., von Burstin V.A., Putoczki T., Bennecke M., Bateman T., et al. gp130-mediated Stat3 activation in enterocytes regulates cell survival and cell-cycle progression during colitis-associated tumorigenesis. Cancer Cell 2009, 15:91-102.
53. Rigby R.J., Simmons J.G., Greenhalgh C.J., Alexander W.S., Lund P.K. Suppressor of cytokine signaling 3 (SOCS3) limits damage-induced crypt hyper-proliferation and inflammation-associated tumorigenesis in the colon. Oncogene 2007, 26:4833-4841.
54. Waldner M.J., Wirtz S., Jefremow A., Warntjen M., Neufert C., Atreya R., et al. VEGF receptor signaling links inflammation and tumorigenesis in colitis-associated cancer. J Exp Med 2010, 207:2855-2868.
55. Corvinus F.M., Orth C., Moriggl R., Tsareva S.A., Wagner S., Pfitzner E.B., et al. Persistent STAT3 activation in colon cancer is associated with enhanced cell proliferation and tumor growth. Neoplasia (New York, NY) 2005, 7:545-555.
56. Komoda H., Tanaka Y., Honda M., Matsuo Y., Hazama K., Takao T. Interleukin-6 levels in colorectal cancer tissues. World J Surg 1998, 22:895-898.
57. Chung Y.-C., Chang Y.-F. Serum interleukin-6 levels reflect the disease status of colorectal cancer. J Surg Oncol 2003, 83:222-226.
58. Galizia G., Orditura M., Romano C., Lieto E., Castellano P., Pelosio L., et al. Prognostic significance of circulating IL-10 and IL-6 serum levels in colon cancer patients undergoing surgery. Clin Immunol (Orlando, FL) 2002, 102:169-178.
59. Knüpfer H., Preiss R. Serum interleukin-6 levels in colorectal cancer patients - a summary of published results. Int J Colorectal Dis 2010, 25:135-140.
60. Belluco C., Nitti D., Frantz M., Toppan P., Basso D., Plebani M., et al. Interleukin-6 blood level is associated with circulating carcinoembryonic antigen and prognosis in patients with colorectal cancer. Ann Surg Oncol 2000, 7:133-138.
61. Tchirkov A., Khalil T., Chautard E., Mokhtari K., Véronèse L., Irthum B., et al. Interleukin-6 gene amplification and shortened survival in glioblastoma patients. Br J Cancer 2007, 96:474-476.
62. Waldner M.J., Neurath M.F. Colitis-associated cancer: the role of T cells in tumor development. Semin Immunopathol 2009, 31:249-256.
63. Eaden J.A., Abrams K.R., Mayberry J.F. The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut 2001, 48:526-535.
64. Canavan C., Abrams K.R., Mayberry J. Meta-analysis: colorectal and small bowel cancer risk in patients with Crohn's disease. Aliment Pharmacol Ther 2006, 23:1097-1104.
65. Wilke C.M., Kryczek I., Wei S., Zhao E., Wu K., Wang G., et al. Th17 cells in cancer: help or hindrance?. Carcinogenesis 2011, 32:643-649.
66. Bromberg J., Wang T.C. Inflammation and cancer: I.L-6 and STAT3 complete the link. Cancer Cell 2009, 15:79-80.
67. Jones S.A., Scheller J., Rose-John S. Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling. J Clin Invest 2011, 121:3375-3383.
68. Mitsuyama K., Matsumoto S., Masuda J., Yamasakii H., Kuwaki K., Takedatsu H., et al. Therapeutic strategies for targeting the IL-6/STAT3 cytokine signaling pathway in inflammatory bowel disease. Anticancer Res 2007, 27:3749-3756.
69. Waetzig G.H., Rose-John S. Hitting a complex target: an update on interleukin-6 trans-signalling. Expert Opin Ther Targets 2012, 16:225-236.
70. Ito H., Takazoe M., Fukuda Y., Hibi T., Kusugami K., Andoh A., et al. A pilot randomized trial of a human anti-interleukin-6 receptor monoclonal antibody in active Crohn's disease. Gastroenterology 2004, 126:989-996. [discussion 947].