Abstract
The etiology of ulcerative colitis (UC) and Crohn's disease (CD) remains enigmatic. Infiltrating intestinal macrophages are capable of producing the proinflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6). We investigated the presence of IL-6, TNF-α and IL-1β mRNA transcripts in inflammatory bowel disease (IBD), normal, and other inflammatory intestinal specimens utilizing the polymerase chain reaction (PCR). TNF-α mRNA levels did not vary between inflammatory bowel disease and control specimens. IL-1β mRNA levels were highest in active UC and noninflammatory bowel disease inflammatory specimens while IL-6 mRNA levels were highest in active IBD specimens. Infiltrating T cells, macrophages, and B cells were identified as sources of IL-6 protein in inflammatory bowel disease specimens by immunofluorescent staining. IL-6 transcripts were elevated only in active inflammatory bowel disease specimens, suggesting that IL-6-mediated immune processes are ongoing in the inflammatory mucosal environment of CD and UC.
Similar content being viewed by others
References
Donowitz M: Arachadonic acid metabolites and their role in inflammatory bowel disease. Gastroenterology 88:580, 1985
Sharon P, Stenson WF: Enhanced synthesis of leukotriene B4 by colonic mucosa in inflammatory bowel disease. Gastroenterology 86:453, 1984
Kitahora T, Suzuki K, Asakura H, Yoshida T, Suematsu, Watanabe M, Aiso S, Tsuchiya M: Active oxygen species generated by monocytes and polymorphonuclear cells in Crohn's disease. Dig Dis Sci 33:951–955, 1988
Broberger O, Perlmann P: Autoantibodies in human ulcerative colitis. J Exp Med 110:657, 1959
Kirsner JB, Shorter RG: Inflammatory Bowel Disease, Philadelphia, Lea & Febiger, 1988
Whorwell PJ, Bennett P, Tanner AR, Wright R: Monocyte function in Crohn's disease and ulcerative colitis. Digestion 22:271–275, 1981
Kurt-Jones EA, Kiely JM, Unanue ER: Conditions required for expression of membrane IL-1 on B-cells. J Immunol 135:1548–1550, 1985
Dinarello CA: Interleukin-1 and its biologically related cytokines. Adv Immunol 44:153–205, 1989
Krane S, Dayer JM, Simon CS, Byrne S: Mononuclear cell-conditioned medium containing mononuclear cell factor (MCF), homologous with interleukin 1, stimulating collagen and fibronectin synthesis by adherent rheumatoid synovial cells: effects of prostaglandin E2 and indomethacin. Collagen Rel Res 5:99–117, 1985
Mahida YR, Wu KC, Jewell DP: Enhanced production of interleukin 1-beta by mononuclear cells isolated from mucosa with active ulcerative colitis or Crohn's disease. Gut 30:835–838, 1989
Ligumsky 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
Pennica D, Nedwin GE, Hayflick JS, Seeburg PH, Derynck R, Palladino MA, Kohr WJ, Aggarwal BB, Goeddel DV: Human tumor necrosis factor: Precursor structure, expression and homology to lymphotoxin. Nature 312:724–729 1984
Scheurich P, Thoma B, Ucer U, Pfizenmaier K: Immunoregulatory activity of recombinant human tumor necrosis factor (TNF)α: Induction of TNF receptors on human T cells and TNFα mediated enhancement of T-cell responses. J Immunol 138:1786–1790, 1987
Jelnick DF, Lipsky PE: Enhancement of human B-cell proliferation and differentiation by tumor necrosis factor α and interleukin 1. J Immunol 139:2970–2976, 1987
Beutler B, Milsark IW, Cerami A: Passive immunization against cachectin/tumor necrosis factor (TNF) protects mice from the lethal effect of endotoxin. Science (Washington, DC) 229:869–871, 1985
Hofman FM, Hinton DR, Johnson K, Merrill JE: Tumor necrosis factor identified in multiple sclerosis brain. J Exp Med 170:607–612 1989
Van Snick J: Interleukin 6: An overview. Annu Rev Immunol 8:253–278, 1990
Raynal MC, Liu Z, Hirano T, Mayer L, Kishimoto T, Chen-Kiang S: Interleukin 6 induces secretion of IgG1 by coordinated transcriptional activation and differential mRNA accumulation. Proc Natl Acad Sci USA 86:8024–8028, 1989
Gauldie J, Richards C, Harnish D, Lansdorp P, Baumann H: Interferon β2/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
Okada M, Kitahara M, Kishimoto S, Matsuda T, Hirano T, Kishimoto T: Il-6/BSF-2 functions as a killer helper factor in thein vitro induction of cytotoxic T cells. J Immunol 141:1543–1549, 1988
Luger TA, Krutmann J, Kirnbauer R, Urbanski A, Schwarz T, Klappacher G, Kock A, Micksche M, Malejczyk J, Schauer E, May LT, Sehgal PB: IFN/IL-6 augments the activity of human natural killer cells. J Immunol 143:1206–1209, 1989
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 glomerulonephtitis. J Immunol 143:3949–3955, 1989
Bataille R, Jourdan M, Zhang XG, Klein B: Serum levels of Interleukin 6, a potent myeloma cell growth factor, as a reflection of disease severity in plasma cell dyscrasia. J Clin Invest 84:2008–2011, 1989
Bhardwaj N, Santhanam U, Lau LL, Tatter SB, Ghrayeb J, Rivelis M, Steinman RM, Sehgal PB, May LT: IL-6/IFN-B2 in synovial effusions of patients with rheumatoid arthritis and other arthritides. J Immunol 143:2153–2159, 1989
Jourdan M, Bataille R, Seguin J, Zhang XG, Chaptal PA, Klein B: Constitutive production of interleukin-6 and immunologic features in cardiac myxomas. Arthritis Rheum 33:398–402, 1990
De Dombal FT, Burton IL, Clamp SE, Goligher JC: Short term course and prognosis of Crohn's disease. Gut 15:435–443, 1974
Glisin V, Crkvenjakov R, Byus D: Ribonucleic acid isolated by cesium chloride centrifugation. Biochemistry 13:2633–2637, 1973
Innis MA, Gelfand DH, Sninsky JJ: PCR Protocols. New York, Academic Press, 1989
Isaacs K, Sartor RB, Wang A, Haskill JS: Profiles of cytokine activation in inflammatory bowel disease tissue: Measurement by cDNA amplification. Gastroenterology 98:455A 1990
Radema SA, van Deventer SJ, Cerami A: Interleukin 1 beta is expressed predominantly by enterocytes in experimental colitis. Gastroenterology 100:1180–1186, 1991
Sartor RB, Chapman EJ, Schwab JH: Increased interleukin-1β concentrations in resected inflammatory bowel disease (IBD) tissue. Gastroenterology 94:399A, 1988
Sehgal PB, Helfgott DC, Santhanam U, Tatter SB, Clarick RH, Ghrayeb J, May LT: Regulation of the acute phase and immune response in viral disease. Enhanced expression of the beta 2-interferon/hepatocyte-stimulating factor/interleukin 6 gene in virus-infected human fibroblasts. J Exp Med 167:1951–1956, 1988
Walz G, Zanker B, Barth C, Wieder KJ, Clark SC, Strom TB: Transcriptional modulation of human IL-6 gene expression by verapamil. J Immunol 144:4242–4248, 1990
Meijer CJ, Bosman FT, Lindeman J: Evidence for predominant involvement of the B-cell systems in the inflammatory process in Crohn's disease. Scand J Gastroenterol 14:21–32, 1979
Wu KC, Mahida YR, Priddle JD, Jewell DP: Effect of human intestinal macrophages on immunoglobulin production by human intestinal mononuclear cells isolated from patients with inflammatory bowel disease. Clin Exp Immunol 79:35–40, 1990
Fiocchi C, Battisto JR, Farmer RG: Studies on isolated gut mucosal lymphocytes in inflammatory bowel disease. Detection of activated T-cells and enhanced proliferation toStaphlococcus aureus and lipopolysaccharides. Dig Dis Sci 26:728–736, 1981
Knudsen PJ, Dinarello CA, Strom TB: Glucocorticoids inhibit transcriptional and post-transcriptional expression of interleukin 1 in U937 cells. J Immunol 139:4129–4134, 1987
Zanker B, Walz G, Wieder KJ, Strom TB: Evidence that glucocorticoids block expression of the human interleukin-6 gene by accessory cells. Transplantation 49:183–185, 1990
Beutler B, Krochin N, Milsark IW, Luedke C, Cerami A: Control of cachectin (tumor necrosis factor) synthesis: Mechanisms of endotoxin resistance. Science 232:977–980, 1986
Lee SW, Tsou AP, Chan H, Thomas J, Petrie K, Eugui EM, Allison AC: Glucocorticoids selectively inhibit the transcription of the interleukin 1β gene and decrease the stability of interleukin 1β mRNA. Proc Natl Acad Sci USA 85:1204–1208, 1988
Almawi WY, Lipman ML, Stevens AC, Zanker B, Hadro ET, Strom TB: Abrogation of glucocorticosteroid-mediated inhibition of T cell proliferation by the synergistic action of IL-1, IL-6, and IFN-γ. J Immunol 146:3523–3527, 1991
Author information
Authors and Affiliations
Additional information
Supported by grants from the NIH, Crohn's and Colitis Foundation of America, Inc., Medical Research Council of Canada, and Deutsche Forschungsgemeinschaft.
Rights and permissions
About this article
Cite this article
Stevens, C., Walz, G., Singaram, C. et al. Tumor necrosis factor-α, interleukin-1β, and interleukin-6 expression in inflammatory bowel disease. Digest Dis Sci 37, 818–826 (1992). https://doi.org/10.1007/BF01300378
Received:
Revised:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF01300378