Contrasting activity of cytosin–guanosin dinucleotide oligonucleotides in mice with experimental colitis

• Published in: Clinical and experimental immunology 2003-11, Vol.134 (2), p.217-224
• Main Authors: OBERMEIER, F., DUNGER, N., STRAUCH, U. G., GRUNWALD, N., HERFARTH, H., SCHÖLMERICH, J., FALK, W.
• Format: Article
• Language: English
• Subjects: Acute Disease; Adjuvants, Immunologic; Animal Studies; Animals; Bacteria; bacterial DNA; Biological and medical sciences; Body Weight; Colitis - immunology; Colitis - pathology; Colitis - prevention & control; Colon - immunology; CpG Islands - immunology; CpG motifs; Dextran Sulfate; dextran sulphate sodium; Disease Models, Animal; experimental colitis; Female; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Immune Tolerance; Immunopathology; Interferon-gamma - biosynthesis; Interleukin-12 - immunology; Interleukin-6 - biosynthesis; Lymph Nodes - immunology; Medical sciences; Mesentery; Mice; Mice, Inbred BALB C; Oligodeoxyribonucleotides - immunology; Oligodeoxyribonucleotides - therapeutic use; Weight Loss
• ISSN: 0009-9104; 1365-2249
• DOI: 10.1046/j.1365-2249.2003.02288.x

SUMMARY 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)‐γ : 11‐fold). In a pretreatment setting CpG‐ODN reduced weight loss significantly and reduced intestinal inflammation by 45%. Colonic IFN‐γ 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‐γ‐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.