Jump to ContentJump to Main Navigation
Show Summary Details

Romanian Journal of Internal Medicine

4 Issues per year

Open Access
Online
ISSN
2501-062X
See all formats and pricing

Cytokines in inflammatory bowel disease

Al.C. Moldoveanu
  • Internal Medicine II and Gastroenterology Clinic, University Hospital Bucharest
  • “Carol Davila” University of Medicine and Pharmacy, Bucharest
/ M. Diculescu
  • Department of Gastroenterology, Fundeni Clinical Institute, Bucharest
  • “Carol Davila” University of Medicine and Pharmacy, Bucharest
/ Carmen Fierbinţeanu Braticevici
  • Corresponding author
  • Internal Medicine II and Gastroenterology Clinic, University Hospital Bucharest
  • “Carol Davila” University of Medicine and Pharmacy, Bucharest
  • Email:
Published Online: 2015-10-14 | DOI: https://doi.org/10.1515/rjim-2015-0016

Abstract

Inflammatory bowel diseases are chronic afflictions, characterized by active and remission periods. Inflammation is the most common type of response that the human body uses as a defense mechanism against aggressors from the environment. The frequency and degree of inflammation depends on the size of the affected tissues. The gastrointestinal tract is, by far, the most susceptible tissue to inflammatory responses, because of its constant exposure to various antigenic, mutagenic and toxic factors.

In inflammatory bowel diseases there is a loss of immune tolerance to intestinal flora that is mediated by various substances, including cytokines. Cytokines represent a key signal in the intestinal immune response. Activated dendritic cells and macrophages secrete cytokines that actively intervene in inflammation regulation, in both Crohn’s disease and ulcerative colitis. After their secretion by antigen presented cells, cytokines activate and differentiate T cells, stirring up the adaptive immune response.

Cytokines have an important role in the pathogenesis of inflammatory bowel diseases. The identification of new cytokines, as well as the changing of the pathogenesis paradigms in inflammatory bowel diseases has been done on animal tests and clinical studies. Thus, there is promising evidence basis for future therapy research based on cytokines, and anti-cytokine antibodies.

Bolile inflamatorii intestinale sunt afecţiuni cronice, caracterizate prin perioade de activitate şi perioade de remisiune. Inflamaţia este cel mai frecvent tip de răspuns al corpului uman ca mecanism de apărare împotriva agresorilor din mediu. Frecvenţa şi gradul de inflamaţie depinde de aria ţesutului afectat. Tractul gastrointestinal este, de departe, cel mai susceptibil ţesut la răspuns inflamator datorită expunerii constante la diverşi factori antigenici, mutagenici sau toxici.

În bolile inflamatorii intestinale există o pierdere a toleranţei imune la flora intestinală care este mediată de diverse substanţe, inclusiv citokinele. Citokinele reprezintă un semnal cheie în răspunsul imun intestinal. Celulele dendritice activate şi macrofagele secretă citokine care intervin activ in reglarea inflamaţiei, atât în boala Crohn cât şi în colita ulcerativă. După secreţia lor de către celulele prezentatoare de antigen, citokinele se activează şi diferenţiază celulele T, activând răspunsul imun dobândit.

Citokinele au un rol important în patogeneza bolilor inflamatorii intestinale. Identificarea unor citokine noi precum şi schimbarea modelelor de patogeneză a bolilor inflamatorii intestinale a fost făcută cu ajutorul testelor pe animale şi a studiilor clinice. Există dovezi promiţătoare pentru cercetarea în viitor a unei terapii bazate pe citokine şi anticorpi anti-citokine.

Keywords: inflammatory bowel disease; immune response; cytokines

REFERENCES

  • 1. FIOCCHI C. Intestinal inflammation: a complex interplay of immune and nonimmune cell interactions. The American journal of physiology. 1997; 273(4 Pt 1):G769-75.

  • 2. FIOCCHI C. Immunity and inflammation: separate or unified? In: MacDermott RP, editor. Clinical Immunology in Gastroenterology and Hepatology: from Bench to Bedside. New Orleans: American Gastroenterological Association; 1994; 182-8.

  • 3. BRANDTZAEG P, HALSTENSEN TS, KETT K, KRAJCI P, KVALE D, ROGNUM TO, et al. Immunobiology and immunopathology of human gut mucosa: humoral immunity and intraepithelial lymphocytes. Gastroenterology. 1989; 97(6):1562-84.

  • 4. GRISHAM MB, YAMADA T. Neutrophils, nitrogen oxides, and inflammatory bowel disease. Annals of the New York Academy of Sciences. 1992; 664:103-15.

  • 5. FIOCCHI CB, DG. KATZ, JA. Cytokine production in the human gastrointestinal tract during inflammation. Current Opinion in Gastroenterology. 1994; 10(6):639-44.

  • 6. RAGHOW R. The role of extracellular matrix in postinflammatory wound healing and fibrosis. FASEB journal: official publication of the Federation of American Societies for Experimental Biology. 1994; 8(11):823-31.

  • 7. SHIMIZU Y, SHAW S. Lymphocyte interactions with extracellular matrix. FASEB journal: official publication of the Federation of American Societies for Experimental Biology. 1991; 5(9):2292-9.

  • 8. LEON F, SMYTHIES LE, SMITH PD, KELSALL BL. Involvement of dendritic cells in the pathogenesis of inflammatory bowel disease. Advances in experimental medicine and biology. 2006; 579:117-32.

  • 9. SANCHEZ-MUNOZ F, DOMINGUEZ-LOPEZ A, YAMAMOTO-FURUSHO JK. Role of cytokines in inflammatory bowel disease. World journal of gastroenterology : WJG. 2008; 14(27):4280-8.

  • 10. XAVIER RJ, PODOLSKY DK. Unravelling the pathogenesis of inflammatory bowel disease. Nature. 2007; 448(7152):427-34.

  • 11. INCE MN, ELLIOTT DE. Immunologic and molecular mechanisms in inflammatory bowel disease. The Surgical clinics of North America. 2007; 87(3):681-96.

  • 12. BREESE E, BRAEGGER CP, CORRIGAN CJ, WALKER-SMITH JA, MACDONALD TT. Interleukin-2- and interferon-gamma-secreting T cells in normal and diseased human intestinal mucosa. Immunology. 1993; 78(1):127-31.

  • 13. FUSS IJ, NEURATH M, BOIRIVANT M, KLEIN JS, DE LA MOTTE C, STRONG SA, 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. Journal of immunology. 1996; 157(3):1261-70.

  • 14. STROBER W, FUSS IJ. Proinflammatory cytokines in the pathogenesis of inflammatory bowel diseases. Gastroenterology. 2011; 140(6):1756-67. [Crossref]

  • 15. BAUMANN H, GAULDIE J. The acute phase response. Immunology today. 1994; 15(2):74-80. [Crossref]

  • 16. BEGUE B, WAJANT H, BAMBOU JC, DUBUQUOY L, SIEGMUND D, BEAULIEU JF, et al. Implication of TNF-related apoptosis-inducing ligand in inflammatory intestinal epithelial lesions. Gastroenterology. 2006;130(7):1962-74.

  • 17. STUCCHI A, REED K, O'BRIEN M, CERDA S, ANDREWS C, GOWER A, et al. A new transcription factor that regulates TNF-alpha gene expression, LITAF, is increased in intestinal tissues from patients with CD and UC. Inflammatory bowel diseases. 2006; 12(7):581-7.

  • 18. REIMUND JM, WITTERSHEIM C, DUMONT S, MULLER CD, BAUMANN R, POINDRON P, et al. Mucosal inflammatory cytokine production by intestinal biopsies in patients with ulcerative colitis and Crohn's disease. Journal of clinical immunology. 1996; 16(3):144-50.

  • 19. YAMAMOTO-FURUSHO JK. Innovative therapeutics for inflammatory bowel disease. World journal of gastroenterology: WJG. 2007; 13(13):1893-6.

  • 20. SPOETTL T, HAUSMANN M, KLEBL F, DIRMEIER A, KLUMP B, HOFFMANN J, et al. Serum soluble TNF receptor I and II levels correlate with disease activity in IBD patients. Inflammatory bowel diseases. 2007; 13(6):727-32.

  • 21. MIZOGUCHI E, HACHIYA Y, KAWADA M, NAGATANI K, OGAWA A, SUGIMOTO K, et al. TNF receptor type I-dependent activation of innate responses to reduce intestinal damage-associated mortality. Gastroenterology. 2008; 134(2):470-80.

  • 22. BAMIAS G, MARTIN C, 3RD, MARINI M, HOANG S, MISHINA M, ROSS WG, et al. Expression, localization, and functional activity of TL1A, a novel Th1-polarizing cytokine in inflammatory bowel disease. Journal of immunology. 2003; 171(9):4868-74.

  • 23. PREHN JL, MEHDIZADEH S, LANDERS CJ, LUO X, CHA SC, WEI P, et al. Potential role for TL1A, the new TNF-family member and potent costimulator of IFN-gamma, in mucosal inflammation. Clinical immunology. 2004;112(1):66-77.

  • 24. KAMADA N, HISAMATSU T, HONDA H, KOBAYASHI T, CHINEN H, TAKAYAMA T, et al. TL1A produced by lamina propria macrophages induces Th1 and Th17 immune responses in cooperation with IL-23 in patients with Crohn's disease. Inflammatory bowel diseases. 2010; 16(4):568-75.

  • 25. PREHN JL, THOMAS LS, LANDERS CJ, YU QT, MICHELSEN KS, TARGAN SR. The T cell costimulator TL1A is induced by FcgammaR signaling in human monocytes and dendritic cells. Journal of immunology. 2007; 178(7):4033-8.

  • 26. MICHELSEN KS, THOMAS LS, TAYLOR KD, YU QT, MEI L, LANDERS CJ, et al. IBD-associated TL1A gene (TNFSF15) haplotypes determine increased expression of TL1A protein. PloS one. 2009; 4(3):e4719.

  • 27. DINARELLO CA. The IL-1 family and inflammatory diseases. Clinical and experimental rheumatology. 2002; 20 (5 Suppl 27): S1-13.

  • 28. ASHWOOD P, HARVEY R, VERJEE T, WOLSTENCROFT R, THOMPSON RP, POWELL JJ. Functional interactions between mucosal IL-1, IL-ra and TGF-beta 1 in ulcerative colitis. Inflammation research : official journal of the European Histamine Research Society [et a.l]. 2004; 53(2):53-9.

  • 29. MITSUYAMA K, TOYONAGA A, SASAKI E, ISHIDA O, IKEDA H, TSURUTA O, et al. Soluble interleukin-6 receptors in inflammatory bowel disease: relation to circulating interleukin-6. Gut. 1995; 36(1):45-9. [Crossref]

  • 30. REINISCH W, GASCHE C, TILLINGER W, WYATT J, LICHTENBERGER C, WILLHEIM M, et al. Clinical relevance of serum interleukin-6 in Crohn's disease: single point measurements, therapy monitoring, and prediction of clinical relapse. The American journal of gastroenterology. 1999; 94(8):2156-64.

  • 31. SUZUKI A, HANADA T, MITSUYAMA K, YOSHIDA T, KAMIZONO S, HOSHINO T, et al. CIS3/SOCS3/SSI3 plays a negative regulatory role in STAT3 activation and intestinal inflammation. The Journal of experimental medicine. 2001; 193(4):471-81.

  • 32. 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. International journal of colorectal disease. 2000; 15(4):206-10.

  • 33. ATREYA R, MUDTER J, FINOTTO S, MULLBERG 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. Nature medicine. 2000; 6(5):583-8.

  • 34. MUDTER J, NEURATH MF. Apoptosis of T cells and the control of inflammatory bowel disease: therapeutic implications. Gut. 2007; 56(2):293-303. [Crossref]

  • 35. KALLEN KJ. The role of transsignalling via the agonistic soluble IL-6 receptor in human diseases. Biochimica et biophysica acta. 2002; 1592(3):323-43.

  • 36. YAMAMOTO M, YOSHIZAKI K, KISHIMOTO T, ITO H. IL-6 is required for the development of Th1 cell-mediated murine colitis. Journal of immunology. 2000; 164(9):4878-82.

  • 37. CAREY R, JURICKOVA I, BALLARD E, BONKOWSKI E, HAN X, XU H, et al. Activation of an IL-6:STAT3-dependent transcriptome in pediatric-onset inflammatory bowel disease. Inflammatory bowel diseases. 2008; 14(4):446-57.

  • 38. LEBEL-BINAY S, BERGER A, ZINZINDOHOUE F, CUGNENC P, THIOUNN N, FRIDMAN WH, et al. Interleukin-18: biological properties and clinical implications. European cytokine network. 2000; 11(1):15-26.

  • 39. LEACH ST, MESSINA I, LEMBERG DA, NOVICK D, RUBENSTEIN M, DAY AS. Local and systemic interleukin-18 and interleukin-18-binding protein in children with inflammatory bowel disease. Inflammatory bowel diseases. 2008; 14(1):68-74.

  • 40. PIZARRO TT, MICHIE MH, BENTZ M, WORARATANADHARM J, SMITH MF, JR., FOLEY E, et al. IL-18, a novel immunoregulatory cytokine, is up-regulated in Crohn's disease: expression and localization in intestinal mucosal cells. Journal of immunology. 1999; 162(11):6829-35.

  • 41. OKAMURA H, KASHIWAMURA S, TSUTSUI H, YOSHIMOTO T, NAKANISHI K. Regulation of interferon-gamma production by IL-12 and IL-18. Current opinion in immunology. 1998; 10(3):259-64.

  • 42. MICALLEF MJ, TANIMOTO T, KOHNO K, IKEGAMI H, KURIMOTO M. Interleukin 18 induces a synergistic enhancement of interferon gamma production in mixed murine spleen cell-tumor cell cultures: role of endogenous interleukin 12. Cancer detection and prevention. 2000; 24(3):234-43.

  • 43. MANGAN PR, HARRINGTON LE, O'QUINN DB, HELMS WS, BULLARD DC, ELSON CO, et al. Transforming growth factor-beta induces development of the T(H)17 lineage. Nature. 2006; 441(7090):231-4.

  • 44. PARADOWSKA A, MASLINISKI W, GRZYBOWSKA-KOWALCZYK A, LACKI J. The function of interleukin 17 in the pathogenesis of rheumatoid arthritis. Archivum immunologiae et therapiae experimentalis. 2007; 55(5):329-34.

  • 45. RUDDY MJ, WONG GC, LIU XK, YAMAMOTO H, KASAYAMA S, KIRKWOOD KL, et al. Functional cooperation between interleukin-17 and tumor necrosis factor-alpha is mediated by CCAAT/enhancer-binding protein family members. The Journal of biological chemistry. 2004; 279(4):2559-67.

  • 46. PARK H, LI Z, YANG XO, CHANG SH, NURIEVA R, WANG YH, et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nature immunology. 2005; 6(11):1133-41.

  • 47. LANGRISH CL, CHEN Y, BLUMENSCHEIN WM, MATTSON J, BASHAM B, SEDGWICK JD, et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. The Journal of experimental medicine. 2005; 201(2):233-40.

  • 48. HONZAWA Y, NAKASE H, SHIOKAWA M, YOSHINO T, IMAEDA H, MATSUURA M, et al. Involvement of interleukin-17A-induced expression of heat shock protein 47 in intestinal fibrosis in Crohn's disease. Gut. 2014;63(12):1902-12.

  • 49. KERAMI Z, DUIJVIS NW, VOGELS EW, VAN DOOREN FH, MOERLAND PD, TE VELDE AA. Effect of interleukin-17 on gene expression profile of fibroblasts from Crohn's disease patients. Journal of Crohn's & colitis. 2014; 8(10):1208-16.

  • 50. JIANG W, SU J, ZHANG X, CHENG X, ZHOU J, SHI R, et al. Elevated levels of Th17 cells and Th17-related cytokines are associated with disease activity in patients with inflammatory bowel disease. Inflammation research : official journal of the European Histamine Research Society [et al]. 2014; 63(11):943-50.

  • 51. FUJINO S, ANDOH A, BAMBA S, OGAWA A, HATA K, ARAKI Y, et al. Increased expression of interleukin 17 in inflammatory bowel disease. Gut. 2003; 52(1):65-70. [Crossref]

  • 52. TRINCHIERI G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nature reviews Immunology. 2003; 3(2):133-46.

  • 53. IIJIMA H, TAKAHASHI I, KISHI D, KIM JK, KAWANO S, HORI M, et al. Alteration of interleukin 4 production results in the inhibition of T helper type 2 cell-dominated inflammatory bowel disease in T cell receptor alpha chain-deficient mice. The Journal of experimental medicine. 1999; 190(5):607-15.

  • 54. GRIGA T, HEBLER U, VOIGT E, TROMM A, MAY B. Interleukin-4 inhibits the increased production of vascular endothelial growth factor by peripheral blood mononuclear cells in patients with inflammatory bowel disease. Hepato-gastroenterology. 2000; 47(36):1604-7.

  • 55. KUHN R, LOHLER J, RENNICK D, RAJEWSKY K, MULLER W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell. 1993; 75(2):263-74. [Crossref]

  • 56. RENNICK DM, FORT MM. Lessons from genetically engineered animal models. XII. IL-10-deficient (IL-10(-/-) mice and intestinal inflammation. American journal of physiology Gastrointestinal and liver physiology. 2000; 278(6):G829-33.

  • 57. MIZOGUCHI A, BHAN AK. A case for regulatory B cells. Journal of immunology. 2006; 176(2):705-10.

  • 58. SATTLER S, LING GS, XU D, HUSSAARTS L, ROMAINE A, ZHAO H, et al. IL-10-producing regulatory B cells induced by IL-33 (Breg(IL-33)) effectively attenuate mucosal inflammatory responses in the gut. Journal of autoimmunity. 2014; 50:107-22.

  • 59. MAREK A, BRODZICKI J, LIBEREK A, KORZON M. TGF-beta (transforming growth factor-beta) in chronic inflammatory conditions - a new diagnostic and prognostic marker? Medical science monitor : international medical journal of experimental and clinical research. 2002; 8(7):RA145-51.

  • 60. KANAZAWA S, TSUNODA T, ONUMA E, MAJIMA T, KAGIYAMA M, KIKUCHI K. VEGF, basic-FGF, and TGF-beta in Crohn's disease and ulcerative colitis: a novel mechanism of chronic intestinal inflammation. The American journal of gastroenterology. 2001; 96(3):822-8.

  • 61. LAWRANCE IC, MAXWELL L, DOE W. Inflammation location, but not type, determines the increase in TGF-beta1 and IGF-1 expression and collagen deposition in IBD intestine. Inflammatory bowel diseases. 2001; 7(1):16-26.

  • 62. FINA D, CARUSO R, PALLONE F, MONTELEONE G. Interleukin-21 (IL-21) controls inflammatory pathways in the gut. Endocrine, metabolic & immune disorders drug targets. 2007; 7(4):288-91.

  • 63. FANTINI MC, MONTELEONE G, MACDONALD TT. New players in the cytokine orchestra of inflammatory bowel disease. Inflammatory bowel diseases. 2007; 13(11):1419-23.

  • 64. DE RHAM C, FERRARI-LACRAZ S, JENDLY S, SCHNEITER G, DAYER JM, VILLARD J. The proinflammatory cytokines IL-2, IL-15 and IL-21 modulate the repertoire of mature human natural killer cell receptors. Arthritis research & therapy. 2007; 9(6):R125.

  • 65. CHEN Z, LAURENCE A, O'SHEA JJ. Signal transduction pathways and transcriptional regulation in the control of Th17 differentiation. Seminars in immunology. 2007; 19(6):400-8.

  • 66. MONTELEONE G, MONTELEONE I, FINA D, VAVASSORI P, DEL VECCHIO BLANCO G, CARUSO R, ET AL. Interleukin-21 enhances T-helper cell type I signaling and interferon-gamma production in Crohn's disease. Gastroenterology. 2005; 128(3):687-94. [Crossref]

  • 67. YESTE A, MASCANFRONI ID, NADEAU M, BURNS EJ, TUKPAH AM, SANTIAGO A, et al. IL-21 induces IL-22 production in CD4+ T cells. Nature communications. 2014; 5:3753.

  • 68. ANDOH A, ZHANG Z, INATOMI O, FUJINO S, DEGUCHI Y, ARAKI Y, et al. Interleukin-22, a member of the IL-10 subfamily, induces inflammatory responses in colonic subepithelial myofibroblasts. Gastroenterology. 2005; 129(3):969-84. [Crossref]

  • 69. SCHMECHEL S, KONRAD A, DIEGELMANN J, GLAS J, WETZKE M, PASCHOS E, et al. Linking genetic susceptibility to Crohn's disease with Th17 cell function: IL-22 serum levels are increased in Crohn's disease and correlate with disease activity and IL23R genotype status. Inflammatory bowel diseases. 2008; 14(2):204-12.

  • 70. SUGIMOTO K, OGAWA A, MIZOGUCHI E, SHIMOMURA Y, ANDOH A, BHAN AK, et al. IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. The Journal of clinical investigation. 2008; 118(2):534-44.

  • 71. LI LJ, GONG C, ZHAO MH, FENG BS. Role of interleukin-22 in inflammatory bowel disease. World journal of gastroenterology : WJG. 2014; 20(48):18177-88.

  • 72. ZINDL CL, LAI JF, LEE YK, MAYNARD CL, HARBOUR SN, OUYANG W, et al. IL-22-producing neutrophils contribute to antimicrobial defense and restitution of colonic epithelial integrity during colitis. Proceedings of the National Academy of Sciences of the United States of America. 2013; 110(31):12768-73.

  • 73. FLOSS DM, MROTZEK S, KLOCKER T, SCHRODER J, GROTZINGER J, ROSE-JOHN S, et al. Identification of canonical tyrosine-dependent and non-canonical tyrosine-independent STAT3 activation sites in the intracellular domain of the interleukin 23 receptor. The Journal of biological chemistry. 2013; 288(27):19386-400.

  • 74. KRYCZEK I, LIN Y, NAGARSHETH N, PENG D, ZHAO L, ZHAO E, et al. IL-22(+)CD4(+) T cells promote colorectal cancer stemness via STAT3 transcription factor activation and induction of the methyltransferase DOT1L. Immunity. 2014; 40(5):772-84.

About the article

Published Online: 2015-10-14

Published in Print: 2015-06-01


Citation Information: Romanian Journal Of Internal Medicine, ISSN (Online) 1220-4749, DOI: https://doi.org/10.1515/rjim-2015-0016. Export Citation

© 2015 Al.C. Moldoveanu et al., published by De Gruyter Open. This chapter is distributed under the terms of the Creative Commons Attribution 4.0 Public License. (CC BY 4.0)

Comments (0)

Please log in or register to comment.
Log in