CpG motifs of bacterial DNA exacerbate colitis of dextran sulfate sodium-treated mice.
Inflammatory bowel disease (IBD) is characterized by a dysregulated intestinal immune response with elevated levels of the Th1 cytokines TNF, IL-12 and IFN-gamma. The luminal flora has been implicated as a major factor contributing to the initiation and perpetuation of chronic intestinal inflammation by as yet unknown mechanisms. Bacterial DNA contains unmethylated cytosine-guanosine dinucleotides (CpG) which strongly activate Th1-mediated immune responses. To test whether these CpG-motifs contribute to intestinal inflammation we treated mice with dextran-sulfate-sodium (DSS)-induced acute or chronic colitis for 5 days with CpG-containing oligodeoxynucleotides (CpG-ODN). Colonic inflammation was assessed by histological scoring. Colonic cytokine RNA was quantified by reverse transcription-PCR and cytokine secretion from mesenterial lymph node cells by ELISA. In chronic colitis, CpG-ODN treatment severely aggravated inflammation by 50%. Colonic expression of IFN-gamma and TNF was elevated (200- and 150-fold, respectively) and IFN-gamma and IL-12 secretion from lymph node cells was increased 5,000- and 8-fold, respectively, compared to GpG-ODN-treated controls. Similar effects were obtained in acute colitis. In conclusion, CpG-motifs of bacterial DNA have proinflammatory activity by strengthening the Th1 arm of immunity in DSS-induced colitis, and might therefore play a significant role in the initiation and perpetuation of inflammation in IBD.
Department of Internal Medicine I, University of Regensburg, Regensburg, Germany.
Florian
F
Obermeier
Nadja
N
Dunger
Ludwig
L
Deml
Hans
H
Herfarth
Jürgen
J
Schölmerich
Werner
W
Falk
D000208:Acute Disease; D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D002908:Chronic Disease; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology*; D018899:CpG Islands / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D004269:DNA, Bacterial / Q000276:immunology*; D016264:Dextran Sulfate / Q000009:adverse effects; D004195:Disease Models, Animal; D005260:Female; D007371:Interferon-gamma / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology; D008643:Mesentery; D051379:Mice; D008807:Mice, Inbred BALB C; D009500:Neutralization Tests; D009838:Oligodeoxyribonucleotides / Q000276:immunology* / Q000494:pharmacology; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology*; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology*; D014407:Tumor Cells, Cultured
D000276:Adjuvants, Immunologic; C408982:CPG-oligonucleotide; D016207:Cytokines; D004269:DNA, Bacterial; D008070:Lipopolysaccharides; D009838:Oligodeoxyribonucleotides; D007371:Interferon-gamma; D016264:Dextran Sulfate