NF-kappaB p65 antisense oligonucleotides may serve as a novel molecular approach for the treatment of patients with ulcerative colitis

Arch Med Res. 2008 Nov;39(8):729-34. doi: 10.1016/j.arcmed.2008.08.001.

Abstract

Background: Activation of nuclear factor-kappa B (NF-kappaB), which controls transcription of various proinflammatory cytokine genes, has been shown to play a critical role in the pathogenesis of ulcerative colitis (UC). The aim of this study was to investigate if NF-kappaB p65 antisense oligonucleotides may affect the expression of NF-kappaB p65 and cytokines in lamina propria mononuclear cells (LPMCs) from patients with UC.

Methods: LPMCs, which were isolated from intestinal mucosal biopsy specimens from patients with UC, were cultured with or without NF-kappaB p65 antisense oligonucleotides, missense oligonucleotides and dexamethasone. NF-kappaB p65 expression was determined by Western blot analysis. The expression of cytokine mRNA was studied by reverse transcription-polymerase chain reaction (RT-PCR). Cytokine levels were measured by enzyme-linked immunosorbent assay.

Results: NF-kappaB p65 antisense oligonucleotides resulted in downregulation of NF-kappaB p65 expression, blocked the expression of IL-1beta mRNA and IL-8 mRNA, and strikingly reduced the production of IL-1beta and IL-8. These effects were greater than those of dexamethasone in cultured LPMCs from patients with UC (p <0.05).

Conclusions: Application of NF-kappaB p65 antisense oligonucleotides may serve as a novel molecular approach for the treatment of patients with UC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Anti-Inflammatory Agents / therapeutic use
  • Colitis, Ulcerative* / metabolism
  • Colitis, Ulcerative* / therapy
  • Dexamethasone / therapeutic use
  • Female
  • Humans
  • Interleukin-1beta / genetics
  • Interleukin-1beta / metabolism
  • Interleukin-8 / genetics
  • Interleukin-8 / metabolism
  • Leukocytes, Mononuclear / cytology
  • Leukocytes, Mononuclear / metabolism
  • Male
  • Middle Aged
  • Mucous Membrane / cytology
  • Mucous Membrane / pathology
  • Oligonucleotides, Antisense / genetics
  • Oligonucleotides, Antisense / metabolism*
  • Oligonucleotides, Antisense / therapeutic use*
  • Transcription Factor RelA / genetics
  • Transcription Factor RelA / metabolism*
  • Transcription Factor RelA / therapeutic use*

Substances

  • Anti-Inflammatory Agents
  • Interleukin-1beta
  • Interleukin-8
  • Oligonucleotides, Antisense
  • Transcription Factor RelA
  • Dexamethasone