Immunostimulatory DNA ameliorates experimental and spontaneous murine colitis.
OBJECTIVE
Impaired mucosal barrier, cytokine imbalance, and dysregulated CD4(+) T cells play important roles in the pathogenesis of experimental colitis and human inflammatory bowel disease. Immunostimulatory DNA sequences (ISS-DNA) and their synthetic oligonucleotide analogs (ISS-ODNs) are derived from bacterial DNA, are potent activators of innate immunity at systemic and mucosal sites, and can rescue cells from death inflicted by different agents. We hypothesized that these combined effects of ISS-DNA could inhibit the damage to the colonic mucosa in chemically induced colitis and thereby limit subsequent intestinal inflammation.


METHODS
The protective and the anti-inflammatory effect of ISS-ODN administration were assessed in dextran sodium sulfate-induced colitis and in 2 models of hapten-induced colitis in Balb/c mice. Similarly, these effects of ISS-ODN were assessed in spontaneous colitis occurring in IL-10 knockout mice.


RESULTS
In all models of experimental and spontaneous colitis examined, ISS-ODN administration ameliorated clinical, biochemical, and histologic scores of colonic inflammation. ISS-ODN administration inhibited the induction of colonic proinflammatory cytokines and chemokines and suppressed the induction of colonic matrix metalloproteinases in both dextran sodium sulfate- and hapten-induced colitis.


CONCLUSIONS
As the colon is continuously exposed to bacterial DNA, these findings suggest a physiologic, anti-inflammatory role for immunostimulatory DNA in the GI tract. Immunostimulatory DNA deserves further evaluation for the treatment of human inflammatory bowel disease.
Rachmilewitz
Daniel
D
Division of Medicine, Shaare Zedek Medical Center, Jerusalem, Israel.
Karmeli
Fanny
F
Takabayashi
Kenji
K
Hayashi
Tomoko
T
Leider-Trejo
Leonor
L
Lee
Jongdae
J
Leoni
Lorenzo M
LM
Raz
Eyal
E
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D003092:Colitis / Q000517:prevention & control*; D051546:Cyclooxygenase 2; D004247:DNA / Q000494:pharmacology*; D005260:Female; D016753:Interleukin-10 / Q000502:physiology; D007527:Isoenzymes / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis; D011453:Prostaglandins / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D000276:Adjuvants, Immunologic; C408982:CPG-oligonucleotide; D007527:Isoenzymes; D009838:Oligodeoxyribonucleotides; D011453:Prostaglandins; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D004247:DNA; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases