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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

Antisense Oligonucleotide Blockade of Tumor Necrosis Factor-α in Two Murine Models of Colitis

Kathleen J. Myers, Sreekant Murthy, Anne Flanigan, Donna R. Witchell, Madeline Butler, Susan Murray, Andrew Siwkowski, Deborah Goodfellow, Karen Madsen and Brenda Baker
Journal of Pharmacology and Experimental Therapeutics January 2003, 304 (1) 411-424; DOI: https://doi.org/10.1124/jpet.102.040329
Kathleen J. Myers
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Sreekant Murthy
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Anne Flanigan
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Donna R. Witchell
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Madeline Butler
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Susan Murray
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Andrew Siwkowski
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Deborah Goodfellow
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Karen Madsen
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Brenda Baker
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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

  • 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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Journal of Pharmacology and Experimental Therapeutics: 304 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 304, Issue 1
1 Jan 2003
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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

Antisense Oligonucleotide Blockade of Tumor Necrosis Factor-α in Two Murine Models of Colitis

Kathleen J. Myers, Sreekant Murthy, Anne Flanigan, Donna R. Witchell, Madeline Butler, Susan Murray, Andrew Siwkowski, Deborah Goodfellow, Karen Madsen and Brenda Baker
Journal of Pharmacology and Experimental Therapeutics January 1, 2003, 304 (1) 411-424; DOI: https://doi.org/10.1124/jpet.102.040329

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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

Antisense Oligonucleotide Blockade of Tumor Necrosis Factor-α in Two Murine Models of Colitis

Kathleen J. Myers, Sreekant Murthy, Anne Flanigan, Donna R. Witchell, Madeline Butler, Susan Murray, Andrew Siwkowski, Deborah Goodfellow, Karen Madsen and Brenda Baker
Journal of Pharmacology and Experimental Therapeutics January 1, 2003, 304 (1) 411-424; DOI: https://doi.org/10.1124/jpet.102.040329
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