Skip to main content
Log in

Elevation of interleukin-6 in inflammatory bowel disease is macrophage- and epithelial cell-dependent

  • Intestinal Disorders, Inflammatory Bowel Disease, Immunology, And Microbiology
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

Local interleukin-6 (IL-6) activity was studied using colonic mucosal tissues in inflammatory bowel disease (IBD) and inflammatory control patients. Active IBD specimens exhibited significantly higher IL-6 activity than control specimens in both cultures of isolated lamina propria mononuclear cells (LPMC) and mucosal tissues with an increased number of IL-6-producing cells. However, the activity in inactive IBD or inflammatory controls did not differ from controls. Northern blot analysis demonstrated IL-6 messenger RNA in LPMC and colonic epithelial cells isolated from active IBD specimens but not in control cells. Furthermore, immunofluorescent microscopic study of active IBD specimens showed more conspicuous staining of IL-6 in infiltrating LPMC (mostly CD68+ cells) and colonic epithelial cells. These results suggest that elevation of local IL-6 activity may be a characteristic feature of active IBD and both macrophages and colonic epithelial cells are the major cell types responsible for this phenomenon.

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

Access this article

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

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Podolsky DK: Inflammatory bowel disease (First of two parts). N Engl J Med 325:928–937, 1991

    PubMed  Google Scholar 

  2. Gross V, Andus T, Leser HG, Roth M, Scholmerich J: Inflammatory mediators in chronic inflammatory bowel diseases. Klin Wochenschr 69:981–987, 1991

    PubMed  Google Scholar 

  3. Schreiber S, McDermott RP, Raedler A, Pinnau R, Bertovich MJ, Nash GS: Increased activation of isolated intestinal lamina propria mononuclear cells in inflammatory bowel disease. Gastroenterology 101:1020–1030, 1991

    PubMed  Google Scholar 

  4. Haruta J, Kusugami K, Kuroiwa A, Ina K, Shinoda M, Morise K, Iokawa H, Morita M, Ishihara A, Sarai S: Phenotypic and functional analysis of lamina propria mononuclear cells from colonoscopic biopsy specimens in patients with ulcerative colitis. Am J Gastroenterol 87:448–454, 1992

    PubMed  Google Scholar 

  5. Allison MC, Poulter LW, Dhillon AP, Pounder RE: Immunohistological studies of surface antigen on colonic lymphoid cells in normal and inflamed mucosa. Comparison of follicular and lamina propria lymphocytes. Gastroenterology 99:421–430, 1990

    PubMed  Google Scholar 

  6. Scott MG, Nahm MH, Macke K, Nash GS, Bertovich MJ, McDermott RP: Spontaneous secretion of IgG subclasses by intestinal mononuclear cells: differences between ulcerative colitis, Crohn's disease, and controls. Clin Exp Immunol 66:209–215, 1986

    PubMed  Google Scholar 

  7. Kishimoto T: The biology of interleukin-6. Blood 74:1–10, 1989

    PubMed  Google Scholar 

  8. Garman RD, Jacobs KA, Clark SC, Raulet DH: B-cell-stimulatory factor 2 (β2 interferon) functions as a second signal for interleukin 2 production by mature murine T cells. Proc Natl Acad Sci USA 84:7629–7633, 1987

    PubMed  Google Scholar 

  9. Vink A, Uyttenhove C, Wauters P, Snick JV: Accessory factors involved in murine T cell activation. Distinct roles of interleukin 6, interleukin 1 and tumor necrosis factor. Eur J Immunol 20:1–6, 1990

    PubMed  Google Scholar 

  10. Tsang KY, Finch MD, Primus FJ, Schlom J: Human recombinant interleukin-6 enhances antibody-dependent cellular cytotoxicity of human tumor cells mediated by human peripheral blood mononuclear cells. Cancer Immunol Immunother 34:9–16, 1991

    PubMed  Google Scholar 

  11. Muraguchi A, Hirano T, Tang B, Matsuda T, Horii Y, Nakajima K, Kishimoto T: The essential role of B cell stimulatory factor 2 (BSF-2/IL-6) for the terminal differentiation of B cells. J Exp Med 167:332–344, 1988

    PubMed  Google Scholar 

  12. Gauldie J, Richards C, Harnish D, Lansdorp P, Baumann H: Interferonβ2/B-cell stimulatory factor type 2 shares identity with monocyte-derived hepatocyte-stimulating factor and regulates the major acute phase protein response in liver cells. Proc Natl Acad Sci USA 84:7251–7255, 1987

    PubMed  Google Scholar 

  13. Mahida YR, Kurlac L, Gallagher A, Hawkey CJ: High circulating concentrations of interleukin-6 in active Crohn's disease but not ulcerative colitis. Gut 32:1531–1534, 1991

    PubMed  Google Scholar 

  14. Gross V, Andus T, Caesar I, Roth M, Scholmerich J: Evidence for continuous stimulation of interleukin-6 production in Crohn's disease. Gastroenterology 102:514–519, 1992

    PubMed  Google Scholar 

  15. Mitsuyama K, Sata M, Tanikawa K: Significance of interleukin-6 in patients with inflammatory bowel disease. Gastroenterol Jpn 26:20–28, 1991

    PubMed  Google Scholar 

  16. Schurmann G, Betzler M, Post S, Herfarth C, Meuer S: Soluble interleukin-2 receptor, interleukin-6 and interleukin-1β in patients with Crohn's disease and ulcerative colitis: Preoperative levels and postoperative changes of serum concentrations. Digestion 51:51–59, 1992

    PubMed  Google Scholar 

  17. Hyams JS, Fitzgerald JE, Treem WR, Wyzga N, Kreutzer DL: Relationship of functional and antigenic interleukin 6 to disease activity in inflammatory bowel disease. Gastroenterology 104:1285–1292, 1993

    PubMed  Google Scholar 

  18. Mitsuyama K, Sasaki E, Toyonaga A, Ikeda H, Tsuruta O, Irie A, Arima N, Oriishi T, Harada K, Fujisaki K, Sata M, Tanikawa K: Colonic mucosal interleukin-6 in inflammatory bowel disease. Digestion 50:104–111, 1991

    PubMed  Google Scholar 

  19. Stevens C, Walz G, Singaram C, Lipman ML, Zanker B, Muggia A, Antonioli D, Peppercorn MA, Strom TB: Tumor necrosis factor-α, interleukin-1β, and interleukin-6 expression in inflammatory bowel disease. Dig Dis Sci 37:818–826, 1992

    PubMed  Google Scholar 

  20. Isaacs KL, Sartor B, Haskill S: Cytokine messenger RNA profiles in inflammatory bowel disease mucosa detected by polymerase chain reaction amplification. Gastroenterology 103:1587–1595, 1992

    PubMed  Google Scholar 

  21. McCabe RP, Secrist H, Botney M, Egan M, Peters MG: Cytokine mRNA expression in intestine from normal and inflammatory bowel disease patients. Clin Immunol Immunopathol 66:52–58, 1993

    PubMed  Google Scholar 

  22. Morson BC, Dawson IMP: Gastrointestinal Pathology. Oxford, Blackwell Scientific Publications, 1979

    Google Scholar 

  23. Gibson PR, van de Pol E, Pullman W, Doe WF: Lysis of colonic epithelial cells by allogenic mononuclear and lymphokine activated killer cells derived from peripheral blood and intestinal mucosa: Evidence against a pathogenic role in inflammatory bowel disease. Gut 29:1076–1084, 1988

    PubMed  Google Scholar 

  24. Kusugami K, Matsuura T, West GA, Youngman KR, Rachmilewitz D, Fiocchi C: Loss of interleukin-2-producing intestinal CD4+ T cells in inflammatory bowel disease. Gastroenterology 101:1594–1605, 1991

    PubMed  Google Scholar 

  25. Kusugami K, Youngman KR, West GA, Fiocchi C: Intestinal immune reactivity to interleukin 2 differs among Crohn's disease, ulcerative colitis, and controls. Gastroenterology 97:1–9, 1989

    PubMed  Google Scholar 

  26. Golder JP, Doe WF: Isolation and preliminary characterization of human intestinal macrophages. Gastroenterology 84:795–802, 1983

    PubMed  Google Scholar 

  27. Thiele D, Kurosaka M, Lipsky PE: Phenotype of the accessory cell necessary for mitogen-stimulated T and B cell responses in human peripheral blood: Delineation by its sensitivity to the lysosomotropic agent,l-leucine methyl ester. J Immunol 131:2282–2290, 1983

    PubMed  Google Scholar 

  28. Ligurnsky M, Simon PL, Karmeli F, Rachmilewitz D: Role of interleukin 1 in inflammatory bowel disease-enhanced production during active disease. Gut 31:686–689, 1990

    PubMed  Google Scholar 

  29. Matsuda T, Hirano T, Kishimoto T: Establishment of an interleukin 6 (IL6)/B cell stimulatory factor 2-dependent cell line and preparation of anti-IL6 monoclonal antibodies. Eur J Immunol 18:951–956, 1988

    PubMed  Google Scholar 

  30. Taguchi T, McGhee JR, Coffman L, Beagley KW, Eldrige JH, Takatsu K, Kiyono H: Analysis of Th1 and Th2 cells in murine gut-associated tissues. Frequencies of CD4+ and CD8+ T cells that secrete IFN-γ and IL-5. J Immunol 145:68–77, 1990

    PubMed  Google Scholar 

  31. Fukatsu A, Matsuo S, Tamai H, Sakamoto N, Matsuda T, Hirano T: Distribution of interleukin-6 in normal and diseased human kidney. Lab Invest 65:61–66, 1991

    PubMed  Google Scholar 

  32. Fukatsu A, Matsuo S, Yuzawa Y, Miyai H, Futenma A, Kato K: Expression of interleukin 6 and major histocompatibility complex molecules in tubular epithelial cells of diseased human kidneys. Lab Invest 69:58–67, 1993

    PubMed  Google Scholar 

  33. Castell JV, Geiger T, Gross V, Andus T, Walter E, Hirano T, Kishimoto T, Heinrich PC: Plasma clearance, organ distribution and target cells of interleukin-6/hepatocyte-stimulating factor in the rat. Eur J Biochem 177:357–361, 1988

    PubMed  Google Scholar 

  34. Linker-Israeli M, Deans RJ, Wallace DJ, Prehn J, Ozeri-Chen T, Klinenberg JR: Elevated levels of endogenous IL-6 in systemic lupus erythematosus. A putative role in pathogenesis. J Immunol 147:117–123, 1991

    PubMed  Google Scholar 

  35. Horii Y, Muraguchi A, Iwano M, Matsuda T, Hirayama T, Yamada H, Fujii Y, Dohi K, Ishikawa H, Ohmoto Y, Yoshizaki K, Hirano T, Kishimoto T: Involvement of IL-6 in mesangial proliferative glomerulonephritis. J Immunol 143:3949–3955, 1989

    PubMed  Google Scholar 

  36. Hirano T, Matsuda T, Turner M, Miyasaka N, Buchan G, Tang B, Sato K, Shimizu M, Maini R, Feldmann M, Kishimoto T: Excessive production of interleukin 6/B cell stimulatory factor-2 in rheumatoid arthritis. Eur J Immunol 18:1797–1801, 1988

    PubMed  Google Scholar 

  37. Bhardwaj N, Santhanam U, Lau LL, Tatter SB, Ghrayeb J, Rivelis M, Steinman RM, Sehgal PB, May LT: IL-6/IFN-β2 in synovial effusions of patients with rheumatoid arthritis and other arthritides. J Immunol 143:2153–2159, 1989

    PubMed  Google Scholar 

  38. Kono Y, Beagley KW, Fujihashi K, McGhee JR, Taga T, Hirano T, Kishimoto T, Kiyono H: Cytokine regulation of localized inflammation. Induction of activated B cells and IL-6-mediated polyclonal IgG and IgA synthesis in inflamed human gingiva. J Immunol 146:1812–1821, 1991

    PubMed  Google Scholar 

  39. Heinrich PC, Castell JV, Andus T: Interleukin-6 and the acute phase response. Biochem J 265:621–636, 1990

    PubMed  Google Scholar 

  40. Mahida YR, Wu K, Jewell DP: Enhanced production of interleukin 1-β by mononuclear cells isolated from mucosa with active ulcerative colitis or Crohn's disease. Gut 30:835–838, 1989

    PubMed  Google Scholar 

  41. MacDonald TT, Hutchings P, Choy MY, Murch S, Cooke A: Tumour necrosis factor-alpha and interferon-gamma production measured at the single cell level in normal and inflamed human intestine. Clin Exp Immunol 81:301–305, 1990

    PubMed  Google Scholar 

  42. Pullman WE, Elsbury S, Kobayashi M, Hapel AJ, Doe WF: Enhanced mucosal cytokine production in inflammatory bowel disease. Gastroenterology 102:55–58, 1992

    Google Scholar 

  43. Olson AD, Ayass M, Chensue S: Tumor necrosis factor and IL-1β expression in pediatric patients with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 16:241–246, 1993

    PubMed  Google Scholar 

  44. Horii Y, Muraguchi A, Suematsu S, Matsuda T, Yoshizaki K, Hirano T, Kishimoto T: Regulation of BSF-2/IL6 production by human mononuclear cells. Macrophage-dependent synthesis of BSF-2/IL6 by T cells. J Immunol 141:1529–1535, 1988

    PubMed  Google Scholar 

  45. Navarro S, Bebili N, Bernaudin JF, Vainchenker W, Doly J: Regulation of the expression of IL-6 in human monocytes. J Immunol 142:4339–4345, 1989

    PubMed  Google Scholar 

  46. Kato K, Yokoi T, Takano N, Kanegane H, Yachie A, Miyawaki T, Taniguchi N: Detection byin situ hybridization and phenotypic characterization of cells expressing IL-6 mRNA in human stimulated blood. J Immunol 144:1317–1322, 1990

    PubMed  Google Scholar 

  47. Choy MY, Walker-Smith JA, Williams CB, MacDonald TT: Differential expression of CD25 (interleukin-2 receptor) on lamina propria T cells and macrophages in the intestinal lesions in Crohn's disease and ulcerative colitis. Gut 31:1365–1370, 1990

    PubMed  Google Scholar 

  48. Malizia G, Calabrese A, Cottone M, Raimondo M, Trejdosiewicz LK, Smart CJ, Oliva L, Pagliaro L: Expression of leukocyte adhesion molecules by mucosal mononuclear phagocytes in inflammatory bowel disease. Gastroenterology 100:150–159, 1991

    PubMed  Google Scholar 

  49. Cappello M, Keshav S, Prince C, Jewell DJ, Gordon S: Detection of mRNAs for macrophage products in inflammatory bowel disease byin situ hybridisation. Gut 33:1214–1219, 1992

    PubMed  Google Scholar 

  50. Shirota K, LeDuy L, Yuan S, Jothy S: Interleukin-6 and its receptor are expressed in human intestinal epithelial cells. Virchows Arch B Cell Pathol 58:303–308, 1990

    Google Scholar 

  51. Selby WS, Janossy G, Mason DY, Jewell DP: Expression of HLA-DR antigens by colonic epithelium in inflammatory bowel disease. Clin Exp Immunol 53:614–618, 1983

    PubMed  Google Scholar 

  52. Mayer L, Eisenhardt D: Lack of induction of suppressor T cells by intestinal epithelial cells from patients with inflammatory bowel disease. J Clin Invest 86:1255–1260, 1990

    PubMed  Google Scholar 

  53. Helfgott DC, May LT, Sthoeger Z, Tamm I, Sehgal PB: Bacterial lipopolysaccharide (endotoxin) enhances expression and secretion ofβ2 interferon by human fibroblasts. J Exp Med 166:1300–1309, 1987

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kusugami, K., Fukatsu, A., Tanimoto, M. et al. Elevation of interleukin-6 in inflammatory bowel disease is macrophage- and epithelial cell-dependent. Digest Dis Sci 40, 949–959 (1995). https://doi.org/10.1007/BF02064182

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02064182

Key words

Navigation