Abstract
Background and aims
Immunoregulatory properties of cytokines may contribute to pathological immune reactions in inflammatory bowel disease. There is an urgent need for a simple and dependable means for quantitating inflammatory activity in mucosal biopsies and assessing relapse risk particularly in patients with active Crohn’s disease (CD).
Patients and methods
Cytokine and chemokine transcripts were quantified using real-time PCR in mucosal biopsy specimens from 70 patients with active inflammatory bowel disease (CD, n=45; ulcerative colitis n=25) and 16 patients with specific colitis (ischemic colitis, infectious colitis). Controls were 12 patients with noninflammatory conditions. CD patients with steroid-induced remission (n=20) were followed for up to 12 months.
Results
Compared to not-inflamed mucosa the vast majority of active CD tissue samples expressed significantly elevated transcript levels of IL-1β, IL-8, IL-23, MRP-14, MIP2α, and MMP-1. Moreover, increased cytokine transcript levels were detected in both active ulcerative colitis and specific colitis. Importantly, TNF-α, IFN-γ, CD40L, and IL-23 transcripts increased in active CD only. Transcript levels (MRP-14, IL-8, MMP-1, MIP2α) were correlated with clinical disease activity (CDAI) and endoscopic scoring indices. Medical treatment induced stable remission in 14 of 20 patients which was paralleled by a reduction in increased transcript levels. All six patients without normalization of MIP2α, MRP-14, TNF-α, and IL-1β transcripts developed an early relapse (n=5) or chronic activity (n=1) during follow-up.
Conclusion
Elevated proinflammatory cytokine transcripts in active CD may underlie disease reactivation and chronicity. Real-time PCR quantification is a simple and objective method for grading inflammation of intestinal mucosa and may be useful in identifying patients who would benefit from anti-inflammatory remission maintenance.
Similar content being viewed by others
References
Sandborn WJ, Feagan BG, Hanauer SB, et al (2002) A review of activity indices and efficacy endpoints for clinical trials of medical therapy in adults with Crohn’s. Gastroenterology 122:512–530
Hanauer SB (1996) Inflammatory bowel disease. N Engl J Med 334:841–848
Sartor RB (1991) Pathogenetic and clinical relevance of cytokines in inflammatory bowel disease. Immunol Res 10:465–471
Fiocchi C (1998) Inflammatory bowel disease: etiology and pathogenesis. Gastroenterology 115:182–205
Fuss IJ, Neurath M, Boirivant M, et al (1996) 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 Immunology 157:1261–1270
Dionne S, Hiscott J, D’Agata I, Duhaime A, Seidman EG (1997) Quantitative PCR analysis of TNF-alpha and IL-1 beta mRNA levels in pediatric IBD mucosal biopsies. Dig Dis Sci 42:1557–1566
Desreumaux P, Brandt E, Gambiez L, et al (1997) Distinct cytokine patterns in early and chronic ileal lesions of Crohn’s disease. Gastroenterology 113:118–126
Stallmach A, Schäfer F, Weber S, et al (1998) Increased state of activation of CD4-positive T cells and elevated interferon-g production in pouchitis. Gut 43:499–505
Schreiber S, Nikolaus S, Hampe J, et al (1999) Tumour necrosis factor alpha and interleukin 1beta in relapse of Crohn’s disease. Lancet 353:459–461
Autschbach F, Giese T, Gassler N, et al (2002) Cytokine/chemokine messenger-RNA expression profiles in ulcerative colitis and Crohn’s disease. Virchows Arch 441:500–513
Rutgeerts P, Hiele M, Geboes K, et al (1995) Controlled trial of metronidazole treatment for prevention of Crohn’s recurrence after ileal resection. Gastroenterology 108:1617–1621
Baron JH, Connell AM, Lennard-Jones JE (1964) Variation between observers in describing mucosal appearance in proctocolitis. BMJ 1:89–92
D’Haens GR, Geboes K, Peeters M, Baert F, Penninckx F, Rutgeerts P (1998) Early lesions of recurrent Crohn’s disease caused by infusion of intestinal contents in excluded ileum. Gastroenterology 114:262–267
Zeitz M (1997) Pathogenesis of inflammatory bowel disease. Digestion 58 [Suppl1]:59–61
Tsukada Y, Nakamura T, Iimura M, et al (2002) Cytokine profile in colonic mucosa of ulcerative colitis correlates with disease activity and response to granulocytapheresis. Am J Gastroenterol 97:2820–2828
Modigliani R, Mary JY, Simon JF, et al (1990) Clinical, biological, and endoscopic picture of attacks of Crohn’s disease. Evolution on prednisolone. Gastroenterology 98:811–818
Sunderkotter C, Kunz M, Steinbrink K, et al (1993) Resistance of mice to experimental leishmaniasis is associated with more rapid appearance of mature macrophages in vitro and in vivo. J Immunol 151:4891–4901
Odink K, Cerletti N, Bruggen J, et al (1987) Two calcium-binding proteins in infiltrate macrophages of rheumatoid arthritis. Nature 330:80–82
Rugtveit J, Brandtzaeg P, Halstensen TS, Fausa O, Scott H (1994) Increased macrophage subset in inflammatory bowel disease: apparent recruitment from peripheral blood monocytes. Gut 35:669–674
Lügering N, Stoll R, Schmid RW, et al (1995) The myeloic related protein MRP8/14 (27E10 antigen)-usefulness as a potential marker for disease activity in ulcerative colitis and putative biological function. Eur J Clin Invest 25:659–664
Lügering N, Stoll R, Kucharzik T, et al (1995) Immunohistochemical distribution and serum levels of the Ca(2+)-binding proteins MRP8, MRP14 and their heterodimeric form MRP8/14 in Crohn’s disease. Digestion 56:406–414
Baugh MD, Perry MJ, Hollander AP, et al (1999) Matrix metalloproteinase levels are elevated in inflammatory bowel disease. Gastroenterology 117:814–822
Lampe B von, Barthel B, Coupland SE, Riecken EO, Rosewicz S (2000) Differential expression of matrix metalloproteinases and their tissue inhibitors in colon mucosa of patients with inflammatory bowel disease. Gut 47:63–73
Stallmach A, Chan CC, Ecker KW, et al (2000) Comparable expression of matrix metalloproteinases 1 and 2 in pouchitis and ulcerative colitis. Gut 47:415–422
Niessner M, Volk BA (1995) Altered Th1/Th2 cytokine profiles in the intestinal mucosa of patients with inflammatory bowel disease as assessed by quantitative reversed transcribed polymerase chain reaction (RT-PCR). Clin Exp Immunol 101:428–435
Brandt E, Colombel JF, Ectors N, Gambiez L, Emilie D, Geboes K, Capron M, Desreumaux P (2000) Enhanced production of IL-8 in chronic but not in early ileal lesions of Crohn’s disease (CD). Clin Exp Immunol 122:180–185
Pages F, Lazar V, Berger A, et al (2001) Analysis of interleukin-18, interleukin-1 converting enzyme (ICE) and interleukin-18 related cytokines in Crohn’s disease lesions. Eur Cytokine Netw 12:97–104
Acknowledgements
The authors thank the nursing staff of the Endoscopy Department for their help in specimen collection. This work was supported in part by a grant from the German Competence Network “Inflammatory Bowel Disease”, AG “Molekulare Marker.”
Author information
Authors and Affiliations
Corresponding author
Additional information
A. Stallmach and T. Giese contributed equally to this work
Rights and permissions
About this article
Cite this article
Stallmach, A., Giese, T., Schmidt, C. et al. Cytokine/chemokine transcript profiles reflect mucosal inflammation in Crohn’s disease. Int J Colorectal Dis 19, 308–315 (2004). https://doi.org/10.1007/s00384-003-0554-4
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00384-003-0554-4