Contrasting activity of cytosin-guanosin dinucleotide oligonucleotides in mice with experimental colitis.
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.
Obermeier
F
F
Department of Internal Medicine I, University of Regensburg, Regensburg, Germany. Florian.Obermeier@klinik.uni-regensburg.de
Dunger
N
N
Strauch
U G
UG
Grunwald
N
N
Herfarth
H
H
Schölmerich
J
J
Falk
W
W
D000208:Acute Disease; D000276:Adjuvants, Immunologic; D000818:Animals; D001835:Body Weight; D003092:Colitis / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D003106:Colon / Q000276:immunology; D018899:CpG Islands / Q000276:immunology; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D005260:Female; D007108:Immune Tolerance; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000276:immunology; D015850:Interleukin-6 / Q000096:biosynthesis; D008198:Lymph Nodes / Q000276:immunology; D008643:Mesentery; D051379:Mice; D008807:Mice, Inbred BALB C; D009838:Oligodeoxyribonucleotides / Q000276:immunology* / Q000627:therapeutic use; D015431:Weight Loss
D000276:Adjuvants, Immunologic; C408982:CPG-oligonucleotide; D015850:Interleukin-6; D009838:Oligodeoxyribonucleotides; D018664:Interleukin-12; D007371:Interferon-gamma; D016264:Dextran Sulfate