Contrasting Activity of Cytosin-Guanosin Dinucleotide Oligonucleotides in Mice With Experimental Colitis

Clin Exp Immunol. 2003 Nov;134(2):217-24. doi: 10.1046/j.1365-2249.2003.02288.x.

Abstract

Intestinal inflammation in inflammatory bowel disease (IBD) and experimental models of colitis is characterized by a dysregulated intestinal immune response with elevated levels of Th1 cytokines. The luminal flora has been implicated as a major factor contributing to the initiation and perpetuation of inflammation in experimental colitis by mechanisms not known. Bacterial DNA contains unmethylated cytosin-guanosin dinucleotides (CpG) which strongly activate Th1-mediated immune responses. To test whether these CpG-motifs modulate intestinal inflammation we treated mice with dextran sulphate sodium (DSS)-induced colitis with CpG-containing oligodeoxynucleotides (CpG-ODN). CpG-ODN given after the onset of DSS colitis aggravated the disease, as indicated by a significantly increased loss of body weight and a 30% increase of the histological score. Further, we found a severe increase of proinflammatory cytokines (interleukin (IL)-6: 40-fold; interferon (IFN)-gamma: 11-fold). In a pretreatment setting CpG-ODN reduced weight loss significantly and reduced intestinal inflammation by 45%. Colonic IFN-gamma and IL-6 mRNA levels were reduced by 75%, and IL-10 was elevated by 400% compared to controls. The prophylactic CpG-effect was not imitated by IL-12 because IL-12 pretreatment was not protective. In time-course experiments, CpG-ODN pretreatment over 5 days resulted in a tolerance effect concerning its IFN-gamma-inducing quality, and during the following days of colitis induction IL-10 secretion from mesenterial lymph node cells was elevated compared to controls. Therefore, the prophylactic effect of CpG-ODN might be explained by its tolerizing effect and/or the increased ability for IL-10 production during the consecutive intestinal inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Adjuvants, Immunologic
  • Animals
  • Body Weight
  • Colitis / immunology*
  • Colitis / pathology
  • Colitis / prevention & control
  • Colon / immunology
  • CpG Islands / immunology
  • Dextran Sulfate
  • Disease Models, Animal
  • Female
  • Immune Tolerance
  • Interferon-gamma / biosynthesis
  • Interleukin-12 / immunology
  • Interleukin-6 / biosynthesis
  • Lymph Nodes / immunology
  • Mesentery
  • Mice
  • Mice, Inbred BALB C
  • Oligodeoxyribonucleotides / immunology*
  • Oligodeoxyribonucleotides / therapeutic use
  • Weight Loss

Substances

  • Adjuvants, Immunologic
  • CPG-oligonucleotide
  • Interleukin-6
  • Oligodeoxyribonucleotides
  • Interleukin-12
  • Interferon-gamma
  • Dextran Sulfate