Abstract
Tumor necrosis factor-α (TNF-α) is a key cytokine involved in the pathogenesis of inflammatory bowel disease. We have developed a second-generation antisense oligonucleotide (ISIS 25302) specific for murine TNF-α and have evaluated this oligonucleotide in two models of gut inflammation of distinct etiology. ISIS 25302 decreased TNF-α mRNA in a dose- and sequence-dependent manner in vitro in the mouse macrophage cell line P388D1. It also reduced TNF-α mRNA in vivo, in whole adipose tissue and in macrophages isolated from the adipose tissue of db/db mice, a strain with constitutively high expression of TNF-α. ISIS 25302 significantly reduced disease activity index scores in mice with both an acute and a chronic form of dextran sodium sulfate (DSS)-induced colitis. It also significantly improved histopathological scores in interleukin (IL)-10-deficient mice. This was accompanied by reductions in both the basal and lipopolysaccharide-stimulated secretion of TNF-α and interferon-γ in colonic organ cultures from IL-10 −/− mice. In this model, efficacy was obtained with both a prophylactic treatment regimen or a therapeutic dosing protocol begun after colitis was already present. In both the DSS and IL-10 −/− models, scrambled and mismatch control oligonucleotides were largely without effect, suggesting that ISIS 25302 was exerting its effects through a sequence-dependent antisense mechanism.
Footnotes
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DOI: 10.1124/jpet.102.040329
- Abbreviations:
- TNF
- tumor necrosis factor
- IL
- interleukin
- IFN-γ
- interferon-γ
- IBD
- inflammatory bowel disease
- DSS
- dextran sodium sulfate
- SCID
- severe combined immunodeficiency
- mAb
- monoclonal antibody
- MOE
- methoxyethyl
- ASO
- antisense oligonucleotide
- LPS
- lipopolysaccharide
- G3PDH
- glyceraldehyde-3-phosphate dehydrogenase
- DAI
- disease activity index
- ICAM-1
- intercellular adhesion molecule-1
- Received July 2, 2002.
- Accepted August 29, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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