A Synthetic TLR4 Antagonist Has Anti-Inflammatory Effects in Two Murine Models of Inflammatory Bowel Disease | Zendy

Madeline Fort | Zendy; Afsaneh Mozaffarian | Zendy; Axel G. Stöver | Zendy; Jean da Silva Correia | Zendy; David A. Johnson | Zendy; Ryan Crane | Zendy; Richard J. Ulevitch | Zendy; David H. Persing | Zendy; Helle BielefeldtOhmann | Zendy; Peter Probst | Zendy; Eric W. Jeffery | Zendy; Steven P. Fling | Zendy; Robert M. Hershberg | Zendy

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A Synthetic TLR4 Antagonist Has Anti-Inflammatory Effects in Two Murine Models of Inflammatory Bowel Disease

Author(s) -

Madeline Fort,

Afsaneh Mozaffarian,

Axel G. Stöver,

Jean da Silva Correia,

David A. Johnson,

Ryan Crane,

Richard J. Ulevitch,

David H. Persing,

Helle BielefeldtOhmann,

Peter Probst,

Eric W. Jeffery,

Steven P. Fling,

Robert M. Hershberg

Publication year - 2005

Publication title -

the journal of immunology

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 2.737

H-Index - 372

eISSN - 1550-6606

pISSN - 0022-1767

DOI - 10.4049/jimmunol.174.10.6416

Subject(s) - tlr4 , inflammation , proinflammatory cytokine , inflammatory bowel disease , immune system , in vivo , innate immune system , immunology , antagonist , pharmacology , chemistry , receptor , biology , medicine , disease , biochemistry , microbiology and biotechnology

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.

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