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A synthetic tlr4 antagonist has anti-inflammatory effects in two murine models of inflammatory bowel disease

Academic Article
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Overview

authors

  • Fort, M. M.
  • Mozaffarian, A.
  • Stover, A. G.
  • da Silva Correia, J.
  • Johnson, D. A.
  • Crane, R. T.
  • Ulevitch, Richard
  • Persing, D. H.
  • Bielefeldt-Ohmann, H.
  • Probst, P.
  • Jeffery, E.
  • Fling, S. P.
  • Hershberg, R. M.

publication date

  • May 2005

journal

  • Journal of Immunology  Journal

abstract

  • Current evidence indicates that the chronic inflammation observed in the intestines of patients with inflammatory bowel disease is due to an aberrant immune response to enteric flora. We have developed a lipid A-mimetic, CRX-526, which has antagonistic activity for TLR4 and can block the interaction of LPS with the immune system. CRX-526 can prevent the expression of proinflammatory genes stimulated by LPS in vitro. This antagonist activity of CRX-526 is directly related to its structure, particularly secondary fatty acyl chain length. In vivo, CRX-526 treatment blocks the ability of LPS to induce TNF-alpha release. Importantly, treatment with CRX-526 inhibits the development of moderate-to-severe disease in two mouse models of colonic inflammation: the dextran sodium sulfate model and multidrug resistance gene 1a-deficient mice. By blocking the interaction between enteric bacteria and the innate immune system, CRX-526 may be an effective therapeutic molecule for inflammatory bowel disease.

subject areas

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Adjuvants, Immunologic
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal
  • Caproates
  • Cells, Cultured
  • Colitis
  • Dextran Sulfate
  • Disease Models, Animal
  • Female
  • Glucosamine
  • HeLa Cells
  • Humans
  • Inflammatory Bowel Diseases
  • Lipid A
  • Lipopolysaccharides
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C3H
  • Mice, Knockout
  • Monocytes
  • Receptors, Immunologic
  • Toll-Like Receptor 4
  • Tumor Necrosis Factor-alpha
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Identity

International Standard Serial Number (ISSN)

  • 0022-1767

PubMed ID

  • 15879143
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Additional Document Info

start page

  • 6416

end page

  • 6423

volume

  • 174

issue

  • 10

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