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Gut. Apr 1998; 42(4): 477–484.
PMCID: PMC1727068

Activation of nuclear factor κB in inflammatory bowel disease

Abstract

Background—Expression of pro-inflammatory cytokines is increased in the intestinal lamina propria of patients with inflammatory bowel disease (IBD). Nuclear factor κB (NFκB) controls transcription of inflammation genes. On activation, NFκB is rapidly released from its cytoplasmic inhibitor (IκB), transmigrates into the nucleus, and binds to DNA response elements in gene promoter regions.
Aims—To investigate whether increased activation of NFκB is important in IBD and may be down-regulated by anti-inflammatory treatment.
Methods—Activation of NFκB was determined by western blot assessment and electrophoretic mobility shift assay in nuclear extracts of colonic biopsy samples as well as lamina propria mononuclear cells.
Results—Nuclear levels of NFκB p65 are increased in lamina propria biopsy specimens from patients with Crohn's disease in comparison with patients with ulcerative colitis and controls. Increased activation of NFκB was detected in lamina propria mononuclear cells from patients with active IBD. Corticosteroids strongly inhibit intestinal NFκB activation in IBD in vivo and in vitro by stabilising the cytosolic inhibitor IκBα against activation induced degradation.
Conclusions—In both IBDs, but particularly Crohn's disease, increased activation of NFκB may be involved in the regulation of the inflammatory response. Inhibition of NFκB activation may represent a mechanism by which steroids exert an anti-inflammatory effect in IBD.

Keywords: interleukin 1ß; inflammatory bowel disease; intestinal immunity; signal transduction; steroids; tumour necrosis factor α

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Selected References

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  • Mahida YR, Wu K, Jewell DP. Enhanced production of interleukin 1-beta by mononuclear cells isolated from mucosa with active ulcerative colitis of Crohn's disease. Gut. 1989 Jun;30(6):835–838. [PMC free article] [PubMed]
  • Ligumsky M, Simon PL, Karmeli F, Rachmilewitz D. Role of interleukin 1 in inflammatory bowel disease--enhanced production during active disease. Gut. 1990 Jun;31(6):686–689. [PMC free article] [PubMed]
  • 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. 1990 Aug;81(2):301–305. [PMC free article] [PubMed]
  • Stevens C, Walz G, Singaram C, Lipman ML, Zanker B, Muggia A, Antonioli D, Peppercorn MA, Strom TB. Tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6 expression in inflammatory bowel disease. Dig Dis Sci. 1992 Jun;37(6):818–826. [PubMed]
  • Isaacs KL, Sartor RB, Haskill S. Cytokine messenger RNA profiles in inflammatory bowel disease mucosa detected by polymerase chain reaction amplification. Gastroenterology. 1992 Nov;103(5):1587–1595. [PubMed]
  • Reinecker HC, Steffen M, Witthoeft T, Pflueger I, Schreiber S, MacDermott RP, Raedler A. Enhanced secretion of tumour necrosis factor-alpha, IL-6, and IL-1 beta by isolated lamina propria mononuclear cells from patients with ulcerative colitis and Crohn's disease. Clin Exp Immunol. 1993 Oct;94(1):174–181. [PMC free article] [PubMed]
  • Nicholls S, Stephens S, Braegger CP, Walker-Smith JA, MacDonald TT. Cytokines in stools of children with inflammatory bowel disease or infective diarrhoea. J Clin Pathol. 1993 Aug;46(8):757–760. [PMC free article] [PubMed]
  • Lenardo MJ, Baltimore D. NF-kappa B: a pleiotropic mediator of inducible and tissue-specific gene control. Cell. 1989 Jul 28;58(2):227–229. [PubMed]
  • Baldwin AS., Jr The NF-kappa B and I kappa B proteins: new discoveries and insights. Annu Rev Immunol. 1996;14:649–683. [PubMed]
  • Hassanain HH, Dai W, Gupta SL. Enhanced gel mobility shift assay for DNA-binding factors. Anal Biochem. 1993 Aug 15;213(1):162–167. [PubMed]
  • Brown K, Gerstberger S, Carlson L, Franzoso G, Siebenlist U. Control of I kappa B-alpha proteolysis by site-specific, signal-induced phosphorylation. Science. 1995 Mar 10;267(5203):1485–1488. [PubMed]
  • Traenckner EB, Wilk S, Baeuerle PA. A proteasome inhibitor prevents activation of NF-kappa B and stabilizes a newly phosphorylated form of I kappa B-alpha that is still bound to NF-kappa B. EMBO J. 1994 Nov 15;13(22):5433–5441. [PMC free article] [PubMed]
  • Scherer DC, Brockman JA, Chen Z, Maniatis T, Ballard DW. Signal-induced degradation of I kappa B alpha requires site-specific ubiquitination. Proc Natl Acad Sci U S A. 1995 Nov 21;92(24):11259–11263. [PMC free article] [PubMed]
  • Kim H, Lee HS, Chang KT, Ko TH, Baek KJ, Kwon NS. Chloromethyl ketones block induction of nitric oxide synthase in murine macrophages by preventing activation of nuclear factor-kappa B. J Immunol. 1995 May 1;154(9):4741–4748. [PubMed]
  • Shakhov AN, Collart MA, Vassalli P, Nedospasov SA, Jongeneel CV. Kappa B-type enhancers are involved in lipopolysaccharide-mediated transcriptional activation of the tumor necrosis factor alpha gene in primary macrophages. J Exp Med. 1990 Jan 1;171(1):35–47. [PMC free article] [PubMed]
  • Kunsch C, Rosen CA. NF-kappa B subunit-specific regulation of the interleukin-8 promoter. Mol Cell Biol. 1993 Oct;13(10):6137–6146. [PMC free article] [PubMed]
  • Ledebur HC, Parks TP. Transcriptional regulation of the intercellular adhesion molecule-1 gene by inflammatory cytokines in human endothelial cells. Essential roles of a variant NF-kappa B site and p65 homodimers. J Biol Chem. 1995 Jan 13;270(2):933–943. [PubMed]
  • Ziegler-Heitbrock HW, Sternsdorf T, Liese J, Belohradsky B, Weber C, Wedel A, Schreck R, Bäuerle P, Ströbel M. Pyrrolidine dithiocarbamate inhibits NF-kappa B mobilization and TNF production in human monocytes. J Immunol. 1993 Dec 15;151(12):6986–6993. [PubMed]
  • Ziegler-Heitbrock HW, Wedel A, Schraut W, Ströbel M, Wendelgass P, Sternsdorf T, Bäuerle PA, Haas JG, Riethmüller G. Tolerance to lipopolysaccharide involves mobilization of nuclear factor kappa B with predominance of p50 homodimers. J Biol Chem. 1994 Jun 24;269(25):17001–17004. [PubMed]
  • Neurath MF, Pettersson S, Meyer zum Büschenfelde KH, Strober W. Local administration of antisense phosphorothioate oligonucleotides to the p65 subunit of NF-kappa B abrogates established experimental colitis in mice. Nat Med. 1996 Sep;2(9):998–1004. [PubMed]
  • Schreiber S, MacDermott RP, Raedler A, Pinnau R, Bertovich MJ, Nash GS. Increased activation of isolated intestinal lamina propria mononuclear cells in inflammatory bowel disease. Gastroenterology. 1991 Oct;101(4):1020–1030. [PubMed]
  • Schreiber S, Heinig T, Panzer U, Reinking R, Bouchard A, Stahl PD, Raedler A. Impaired response of activated mononuclear phagocytes to interleukin 4 in inflammatory bowel disease. Gastroenterology. 1995 Jan;108(1):21–33. [PubMed]
  • Hou J, Schindler U, Henzel WJ, Ho TC, Brasseur M, McKnight SL. An interleukin-4-induced transcription factor: IL-4 Stat. Science. 1994 Sep 16;265(5179):1701–1706. [PubMed]
  • Scholtz B, Lamb K, Rosfjord E, Kingsley M, Rizzino A. Appearance of nuclear protease activity after embryonal carcinoma cells undergo differentiation. Dev Biol. 1996 Feb 1;173(2):420–427. [PubMed]
  • Dent CL, Latchman DS. The overlapping octamer/TAATGARAT motif is a high-affinity binding site for the cellular transcription factors Oct-1 and Oct-2. Biochem J. 1991 Jul 15;277(Pt 2):541–545. [PMC free article] [PubMed]
  • Henell F, Glaumann H. Effect of leupeptin on the autophagic vacuolar system of rat hepatocytes. Correlation between ultrastructure and degradation of membrane and cytosolic proteins. Lab Invest. 1984 Jul;51(1):46–56. [PubMed]
  • LOWRY OH, ROSEBROUGH NJ, FARR AL, RANDALL RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed]
  • Rohringer R, Holden DW. Protein blotting: detection of proteins with colloidal gold, and of glycoproteins and lectins with biotin-conjugated and enzyme probes. Anal Biochem. 1985 Jan;144(1):118–127. [PubMed]
  • Fried MG. Measurement of protein-DNA interaction parameters by electrophoresis mobility shift assay. Electrophoresis. 1989 May-Jun;10(5-6):366–376. [PubMed]
  • van Dullemen HM, van Deventer SJ, Hommes DW, Bijl HA, Jansen J, Tytgat GN, Woody J. Treatment of Crohn's disease with anti-tumor necrosis factor chimeric monoclonal antibody (cA2). Gastroenterology. 1995 Jul;109(1):129–135. [PubMed]
  • Scheinman RI, Cogswell PC, Lofquist AK, Baldwin AS., Jr Role of transcriptional activation of I kappa B alpha in mediation of immunosuppression by glucocorticoids. Science. 1995 Oct 13;270(5234):283–286. [PubMed]
  • Auphan N, DiDonato JA, Rosette C, Helmberg A, Karin M. Immunosuppression by glucocorticoids: inhibition of NF-kappa B activity through induction of I kappa B synthesis. Science. 1995 Oct 13;270(5234):286–290. [PubMed]
  • Kopp E, Ghosh S. Inhibition of NF-kappa B by sodium salicylate and aspirin. Science. 1994 Aug 12;265(5174):956–959. [PubMed]
  • Best WR, Becktel JM, Singleton JW, Kern F., Jr Development of a Crohn's disease activity index. National Cooperative Crohn's Disease Study. Gastroenterology. 1976 Mar;70(3):439–444. [PubMed]
  • Rachmilewitz D. Coated mesalazine (5-aminosalicylic acid) versus sulphasalazine in the treatment of active ulcerative colitis: a randomised trial. BMJ. 1989 Jan 14;298(6666):82–86. [PMC free article] [PubMed]

Figures and Tables

Figure 1
NFκB p65 in nuclear extracts from colonic biospsy samples. Colonic biopsy specimens from 10 patients with active Crohn's disease (CD), 14 patients with active ulcerative colitis (UC), six disease specificity controls (DSC), and seven normal controls ...
Figure 2
Total NFκB p65 and IκBα in colonic biospy tissue. Colonic biopsy specimens were homogenised and analysed by western blot without prior compartmentalised extraction. Densitometric readings are shown by the bar graph (mean (SD)). ...
Figure 3
Detection of NFκB in the intestinal lamina propria. (A) Nuclear extracts were prepared from colonoscopic biopsy specimens. A representative radioactive electrophoretic mobility shift assay using consensus oligonucleotides to detect NFκ ...
Figure 4
Inhibition of NFκB activation (A) and IκBα degradation (B) by steroids (dexamethasone) and N-α-tosyl-phenylalanine chloromethyl ketone (TPCK). Nuclear extracts were prepared from lamnia propria mononuclear cells obtained ...
Figure 5
Nuclear NFκB p65 from colonoscopic biopsy specimens from patients with inflammatory bowel disease is decreased by steroid treatment. Sigmoid biopsy specimens were obtained from patients with moderately to highly active ileocolonic Crohn's disease ...
Figure 6
Schematic representation of NFκB activation and inhibition by steroids. Activating stimuli including tumour necrosis factor α (TNF-α) and lipopolysaccharide (LPS) promote degradation of IκBα and the subsequent release ...

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