Skip to main content
Top
Published in: International Journal of Colorectal Disease 9/2007

01-09-2007 | Original Article

Interleukin-18 is increased only in a minority of patients with active Crohn’s disease

Authors: C. Schmidt, T. Giese, R. Goebel, M. Schilling, T. Marth, A. Ruether, S. Schreiber, S. Zeuzem, S. C. Meuer, A. Stallmach

Published in: International Journal of Colorectal Disease | Issue 9/2007

Login to get access

Abstract

Background and aims

It has been suggested that Crohn’s Disease (CD) is associated with an elevated T helper 1 response as manifested by increased production of interleukin-18 (IL-18). Local concentrations of neutralizing IL-18 binding proteins (IL-18bp) may counteract biological functions of mature IL-18 in mucosal inflammation. Therefore, we investigated the IL-18/IL-18bp system in a large group of patients with active inflammatory bowel disease (IBD) to identify patients that could respond theoretically to IL-18 neutralizing treatment strategies.

Patient/methods

IL-18 and IL-18bp messenger RNA (mRNA) expression in colonic mucosa from patients with active CD (n = 72), active ulcerative colitis (UC; n = 32), and non-IBD controls (infectious colitis or diverticulitis; n = 19) and normal, non-diseased controls (n = 20) were measured by reverse-transcribed real-time polymerase chain reaction. Mature IL-18 protein and IL-18bp expression in inflamed mucosa were assessed by Western blotting.

Results/findings

Although IL-18 mRNA was increased in some patients with CD, the increase was not statistically significant. Densitometric evaluation of IL-18/α-actin ratio in patients with active CD (n = 20) and patients with UC (n = 10) demonstrated an increased ratio of IL-18 protein in CD when compared to UC (1.04 vs 0.72 [median]). On closer inspections, only 7/20 CD patients had an increased IL-18 protein expression in inflamed areas compared to noninflamed mucosa.

Interpretation/conclusion

IL-18 expression in active CD is heterogeneous, only a minority of patients expresses elevated levels. Further treatment strategies targeting IL-18 expression in active CD should be concentrated on this subgroup of patients.
Literature
1.
go back to reference Zeitz M (1997) Pathogenesis of inflammatory bowel disease. Digestion 58(Suppl 1):59–61PubMed Zeitz M (1997) Pathogenesis of inflammatory bowel disease. Digestion 58(Suppl 1):59–61PubMed
2.
go back to reference Fiocchi C (1989) Inflammatory bowel disease: Etiology and pathogenesis. Gastroenterology 115:182–205CrossRef Fiocchi C (1989) Inflammatory bowel disease: Etiology and pathogenesis. Gastroenterology 115:182–205CrossRef
3.
go back to reference Breese E, Braegger CP, Corrigan CJ et al (1993) Interleukin2 and interferongammasecreting T cells in normal and diseased human intestinal mucosa. Immunology 78:127–131PubMed Breese E, Braegger CP, Corrigan CJ et al (1993) Interleukin2 and interferongammasecreting T cells in normal and diseased human intestinal mucosa. Immunology 78:127–131PubMed
4.
go back to reference 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 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
5.
go back to reference Stallmach A, Marth T, Adrian T et al (2002) Increased expression of IL-12 receptor ß2 mRNA in lamina propria mononuclear cells of patients with active Crohn’s disease. Int J Colorectal Dis 17:303–310PubMedCrossRef Stallmach A, Marth T, Adrian T et al (2002) Increased expression of IL-12 receptor ß2 mRNA in lamina propria mononuclear cells of patients with active Crohn’s disease. Int J Colorectal Dis 17:303–310PubMedCrossRef
6.
go back to reference Okamura H, Tsutsi H, Komatsu T et al (1995) Cloning of a new cytokine that induces IFN-gamma production by T cells. Nature 378:88–91PubMedCrossRef Okamura H, Tsutsi H, Komatsu T et al (1995) Cloning of a new cytokine that induces IFN-gamma production by T cells. Nature 378:88–91PubMedCrossRef
7.
go back to reference Ushio S, Namba M, Okura T et al (1996) Cloning of the cDNA for human IFN-gamma-inducing factor, expression in Escherichia coli, and studies on the biologic activities of the protein. J Immunol 156:4274–4279PubMed Ushio S, Namba M, Okura T et al (1996) Cloning of the cDNA for human IFN-gamma-inducing factor, expression in Escherichia coli, and studies on the biologic activities of the protein. J Immunol 156:4274–4279PubMed
8.
go back to reference Gu Y, Kuida K, Tsutsui H et al (1997) Activation of interferon-gamma inducing factor mediated by interleukin-1beta converting enzyme. Science 275:206–209PubMedCrossRef Gu Y, Kuida K, Tsutsui H et al (1997) Activation of interferon-gamma inducing factor mediated by interleukin-1beta converting enzyme. Science 275:206–209PubMedCrossRef
9.
go back to reference Kohno K, Kataoka J, Ohtsuki T et al (1997) IFN-gamma-inducing factor (IGIF) is a costimulatory factor on the activation of Th1 but not Th2 cells and exerts its effect independently of IL-12. J Immunol 158:1541–1550PubMed Kohno K, Kataoka J, Ohtsuki T et al (1997) IFN-gamma-inducing factor (IGIF) is a costimulatory factor on the activation of Th1 but not Th2 cells and exerts its effect independently of IL-12. J Immunol 158:1541–1550PubMed
10.
go back to reference Matikainen S, Paananen A, Miettinen M et al (2001) IFN-alpha and IL-18 synergistically enhance IFN-gamma production in human NK cells: differential regulation of Stat4 activation and IFN-gamma gene expression by IFN-alpha and IL-12. Eur J Immunol 31:2236–2245PubMedCrossRef Matikainen S, Paananen A, Miettinen M et al (2001) IFN-alpha and IL-18 synergistically enhance IFN-gamma production in human NK cells: differential regulation of Stat4 activation and IFN-gamma gene expression by IFN-alpha and IL-12. Eur J Immunol 31:2236–2245PubMedCrossRef
11.
go back to reference Nakahira M, Ahn HJ, Park WR et al (2002) Synergy of IL-12 and IL-18 for IFN-gamma gene expression: IL-12-induced STAT4 contributes to IFN-gamma promoter activation by up-regulating the binding activity of IL-18-induced activator protein 1. J Immunol 168:1146–1153PubMed Nakahira M, Ahn HJ, Park WR et al (2002) Synergy of IL-12 and IL-18 for IFN-gamma gene expression: IL-12-induced STAT4 contributes to IFN-gamma promoter activation by up-regulating the binding activity of IL-18-induced activator protein 1. J Immunol 168:1146–1153PubMed
12.
go back to reference Monteleone G, Trapasso F, Parrello T et al (1999) Bioactive IL-18 expression is up-regulated in Crohn’s disease. J Immunol 163:143–147PubMed Monteleone G, Trapasso F, Parrello T et al (1999) Bioactive IL-18 expression is up-regulated in Crohn’s disease. J Immunol 163:143–147PubMed
13.
go back to reference Pizarro TT, Michie MH, Bentz M et al (1999) IL-18, a novel immunoregulatory cytokine, is up-regulated in Crohn’s disease: expression and localization in intestinal mucosal cells. J Immunol 162:6829–6835PubMed Pizarro TT, Michie MH, Bentz M et al (1999) IL-18, a novel immunoregulatory cytokine, is up-regulated in Crohn’s disease: expression and localization in intestinal mucosal cells. J Immunol 162:6829–6835PubMed
14.
go back to reference Kanai T, Watanabe M, Okazawa A et al (2000) Interleukin 18 is a potent proliferative factor for intestinal mucosal lymphocytes in Crohn’s disease. Gastroenterology 119:1514–1523PubMedCrossRef Kanai T, Watanabe M, Okazawa A et al (2000) Interleukin 18 is a potent proliferative factor for intestinal mucosal lymphocytes in Crohn’s disease. Gastroenterology 119:1514–1523PubMedCrossRef
15.
go back to reference Kanai T, Watanabe M, Okazawa A et al (2001) Macrophage-derived IL-18-mediated intestinal inflammation in the murine model of Crohn’s disease. Gastroenterology 121:875–888PubMedCrossRef Kanai T, Watanabe M, Okazawa A et al (2001) Macrophage-derived IL-18-mediated intestinal inflammation in the murine model of Crohn’s disease. Gastroenterology 121:875–888PubMedCrossRef
16.
go back to reference Ten Hove T, Corbaz A, Amitai H et al (2001) Blockade of endogenous IL-18 ameliorates TNBS-induced colitis by decreasing local TNF-alpha production in mice. Gastroenterology 121:1372–1379PubMedCrossRef Ten Hove T, Corbaz A, Amitai H et al (2001) Blockade of endogenous IL-18 ameliorates TNBS-induced colitis by decreasing local TNF-alpha production in mice. Gastroenterology 121:1372–1379PubMedCrossRef
17.
go back to reference Sivakumar PV, Westrich GM, Kanaly S et al (2002) Interleukin 18 is a primary mediator of the inflammation associated with dextran sulphate sodium induced colitis: blocking interleukin 18 attenuates intestinal damage. Gut 50:812–820PubMedCrossRef Sivakumar PV, Westrich GM, Kanaly S et al (2002) Interleukin 18 is a primary mediator of the inflammation associated with dextran sulphate sodium induced colitis: blocking interleukin 18 attenuates intestinal damage. Gut 50:812–820PubMedCrossRef
18.
go back to reference Siegmund B, Fantuzzi G, Rieder F et al (2001) Neutralization of interleukin-18 reduces severity in murine colitis and intestinal IFN-gamma and TNF-alpha production. Am J Physiol Regul Integr Comp Physiol 281:R1264–R1273PubMed Siegmund B, Fantuzzi G, Rieder F et al (2001) Neutralization of interleukin-18 reduces severity in murine colitis and intestinal IFN-gamma and TNF-alpha production. Am J Physiol Regul Integr Comp Physiol 281:R1264–R1273PubMed
19.
go back to reference Wirtz S, Becker C, Blumberg R et al (2002) Treatment of T cell-dependent experimental colitis in SCID mice by local administration of an adenovirus expressing IL-18 antisense mRNA. J Immunol 168:411–420PubMed Wirtz S, Becker C, Blumberg R et al (2002) Treatment of T cell-dependent experimental colitis in SCID mice by local administration of an adenovirus expressing IL-18 antisense mRNA. J Immunol 168:411–420PubMed
20.
go back to reference Rutgeerts P, Hiele M, Geboes K et al (1995) Controlled trial of metronidazole treatment for prevention of Crohn’s recurrence after ileal resection. Gastroenterology 108:1617–1621PubMedCrossRef Rutgeerts P, Hiele M, Geboes K et al (1995) Controlled trial of metronidazole treatment for prevention of Crohn’s recurrence after ileal resection. Gastroenterology 108:1617–1621PubMedCrossRef
21.
go back to reference Baron JH, Connell AM, Lennard-Jones JE (1964) Variation between observers in describing mucosal appearance in proctocolitis. Br Med J 1:89–92PubMed Baron JH, Connell AM, Lennard-Jones JE (1964) Variation between observers in describing mucosal appearance in proctocolitis. Br Med J 1:89–92PubMed
22.
go back to reference Targan SR, Hanauer SB, van Deventer SJ et al (1997) A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn’s disease. Crohn’s Disease cA2 Study Group. N Engl J Med 337:1029–1035PubMedCrossRef Targan SR, Hanauer SB, van Deventer SJ et al (1997) A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn’s disease. Crohn’s Disease cA2 Study Group. N Engl J Med 337:1029–1035PubMedCrossRef
23.
go back to reference Hanauer SB, Feagan BG, Lichtenstein GR et al (2002) Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet 359:1541–1549PubMedCrossRef Hanauer SB, Feagan BG, Lichtenstein GR et al (2002) Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet 359:1541–1549PubMedCrossRef
24.
go back to reference Brown SL, Greene MH, Gershon SK et al (2002) Tumor necrosis factor antagonist therapy and lymphoma development: twenty-six cases reported to the Food and Drug Administration. Arthritis Rheum 46:3151–3158PubMedCrossRef Brown SL, Greene MH, Gershon SK et al (2002) Tumor necrosis factor antagonist therapy and lymphoma development: twenty-six cases reported to the Food and Drug Administration. Arthritis Rheum 46:3151–3158PubMedCrossRef
25.
go back to reference Esters N, Vermeire S, Joossens S et al (2002) Serological markers for prediction of response to anti-tumor necrosis factor treatment in Crohn’s disease. Am J Gastroenterol 97:1458–1462PubMedCrossRef Esters N, Vermeire S, Joossens S et al (2002) Serological markers for prediction of response to anti-tumor necrosis factor treatment in Crohn’s disease. Am J Gastroenterol 97:1458–1462PubMedCrossRef
26.
go back to reference Vermeire S, Louis E, Rutgeerts P et al (2002) NOD2/CARD15 does not influence response to infliximab in Crohn’s disease. Gastroenterology 123:106–111PubMedCrossRef Vermeire S, Louis E, Rutgeerts P et al (2002) NOD2/CARD15 does not influence response to infliximab in Crohn’s disease. Gastroenterology 123:106–111PubMedCrossRef
27.
go back to reference Desreumaux P, Brandt E, Gambiez L et al (1997) Distinct cytokine patterns in early and chronic ileal lesions of Crohn’s disease. Gastroenterology 113:118–126PubMedCrossRef Desreumaux P, Brandt E, Gambiez L et al (1997) Distinct cytokine patterns in early and chronic ileal lesions of Crohn’s disease. Gastroenterology 113:118–126PubMedCrossRef
28.
go back to reference Schmidt C, Giese T, Ludwig B et al (2005) Expression of IL-12 related cytokines in IBD: Elevated IL-23p19 and IL-27p28 in Crohn’s disease but not in ulcerative colitis. Inflamm Bowel Dis 11:16–23PubMedCrossRef Schmidt C, Giese T, Ludwig B et al (2005) Expression of IL-12 related cytokines in IBD: Elevated IL-23p19 and IL-27p28 in Crohn’s disease but not in ulcerative colitis. Inflamm Bowel Dis 11:16–23PubMedCrossRef
29.
go back to reference Sugiura T, Kawaguchi Y, Harigai M et al (2002) Association between adult-onset Still’s disease and interleukin-18 gene polymorphisms. Genes Immun 3:394–399PubMedCrossRef Sugiura T, Kawaguchi Y, Harigai M et al (2002) Association between adult-onset Still’s disease and interleukin-18 gene polymorphisms. Genes Immun 3:394–399PubMedCrossRef
30.
go back to reference Takada T, Suzuki E, Morohashi K et al (2002) Association of single nucleotide polymorphisms in the IL-18 gene with sarcoidosis in a Japanese population. Tissue Antigens 60:36–42PubMedCrossRef Takada T, Suzuki E, Morohashi K et al (2002) Association of single nucleotide polymorphisms in the IL-18 gene with sarcoidosis in a Japanese population. Tissue Antigens 60:36–42PubMedCrossRef
31.
go back to reference Kretowski A, Mironczuk K, Karpinska A et al (2002) Interleukin-18 promoter polymorphisms in type 1 diabetes. Diabetes 51:3347–3349PubMedCrossRef Kretowski A, Mironczuk K, Karpinska A et al (2002) Interleukin-18 promoter polymorphisms in type 1 diabetes. Diabetes 51:3347–3349PubMedCrossRef
32.
go back to reference Haas SL, Hoch AW, Schreiber S et al (2005) -137 (G/C) IL-18 promotor polymorphism in patients with inflammatory bowel disease. Scand J Gastroenterol 40:1438–1443PubMedCrossRef Haas SL, Hoch AW, Schreiber S et al (2005) -137 (G/C) IL-18 promotor polymorphism in patients with inflammatory bowel disease. Scand J Gastroenterol 40:1438–1443PubMedCrossRef
33.
go back to reference Corbaz A, ten Hove T, Herren S et al (2002) IL-18-binding protein expression by endothelial cells and macrophages is up-regulated during active Crohn’s disease. J Immunol 168:3608–3616PubMed Corbaz A, ten Hove T, Herren S et al (2002) IL-18-binding protein expression by endothelial cells and macrophages is up-regulated during active Crohn’s disease. J Immunol 168:3608–3616PubMed
34.
go back to reference Ludwiczek O, Vannier E, Borggraefe I et al (2004) Imbalance between interleukin-1 agonists and antagonists: relationship to severity of inflammatory bowel disease. Clin Exp Immunol 138:323–329PubMedCrossRef Ludwiczek O, Vannier E, Borggraefe I et al (2004) Imbalance between interleukin-1 agonists and antagonists: relationship to severity of inflammatory bowel disease. Clin Exp Immunol 138:323–329PubMedCrossRef
35.
go back to reference Novick, D, Kim SH, Fantuzzi G et al (1999) Interleukin-18 binding protein: a novel modulator of the Th1 cytokine response. Immunity 10:127PubMedCrossRef Novick, D, Kim SH, Fantuzzi G et al (1999) Interleukin-18 binding protein: a novel modulator of the Th1 cytokine response. Immunity 10:127PubMedCrossRef
36.
go back to reference Kim SH, Eisenstein M, Reznikov L et al (2000) Structural requirements of six naturally occurring isoforms of the IL-18 binding protein to inhibit IL-18. Proc Natl Acad Sci USA 97:1190PubMedCrossRef Kim SH, Eisenstein M, Reznikov L et al (2000) Structural requirements of six naturally occurring isoforms of the IL-18 binding protein to inhibit IL-18. Proc Natl Acad Sci USA 97:1190PubMedCrossRef
37.
go back to reference Ludwiczek O, Kaser A, Novick D et al (2005) Elevated systemic levels of free interleukin-18 (IL-18) in patients with Crohn’s disease. Eur Cytokine Netw 16:27–33PubMed Ludwiczek O, Kaser A, Novick D et al (2005) Elevated systemic levels of free interleukin-18 (IL-18) in patients with Crohn’s disease. Eur Cytokine Netw 16:27–33PubMed
Metadata
Title
Interleukin-18 is increased only in a minority of patients with active Crohn’s disease
Authors
C. Schmidt
T. Giese
R. Goebel
M. Schilling
T. Marth
A. Ruether
S. Schreiber
S. Zeuzem
S. C. Meuer
A. Stallmach
Publication date
01-09-2007
Publisher
Springer-Verlag
Published in
International Journal of Colorectal Disease / Issue 9/2007
Print ISSN: 0179-1958
Electronic ISSN: 1432-1262
DOI
https://doi.org/10.1007/s00384-007-0282-2

Other articles of this Issue 9/2007

International Journal of Colorectal Disease 9/2007 Go to the issue