A synthetic TLR4 antagonist has anti-inflammatory effects in two murine models of inflammatory bowel disease
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.
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Treatment with the TLR4 antagonist CRX-526 inhibited the development of disease in an acute DSS colitis model.
“Importantly, treatment with a TLR4 antagonist (CRX-526) inhibited the development of disease in an acute DSS colitis model.108”
From Regulation of Intestinal Barrier Function by Microbial Metabolites (2021) · cites this paper as [108]
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- Authors
- Fort, M. M., Mozaffarian, A., Stöver, A. G., Correia, J. D. S., Johnson, D. A., Crane, R. T., Ulevitch, R. J., Persing, D. H., Bielefeldt-Ohmann, H., Probst, P., Jeffery, E., Fling, S. P., & Hershberg, R. M.
- Affiliations
- Scripps Research Institute (US)
- Corixa Corporation , Seattle, WA 98101
- Washington National Primate Research Center, University of Washington , Seattle, WA 98195
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2005-05
- Volume
- 174
- Issue
- 10
- Pages
- 6416-6423
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W1906569767
- Cited by
- 216
- References
- 38
- Citations by year
- 2026: 5 · 2025: 1 · 2024: 3 · 2023: 5 · 2022: 13 · 2021: 8 · 2020: 8 · 2019: 8 · 2018: 8 · 2017: 9 · 2016: 5 · 2015: 5 · 2014: 12 · 2013: 15 · 2012: 10
- FWCI
- 6.64
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Keywords
- TLR4 antagonist, inflammatory bowel disease, lipopolysaccharide, TNF-α, DSS-induced colitis, innate immunity, enteric bacteria, anti-inflammatory therapy, acyl chain length
- MeSH terms
- Adjuvants, Immunologic, Animals, Anti-Inflammatory Agents, Non-Steroidal, Caproates, Cells, Cultured, Colitis, Disease Models, Animal, Female, Glucosamine, HeLa Cells, Humans, Lipid A, Lipopolysaccharides, Mice, Inbred BALB C, Mice, Inbred C3H, Monocytes, Receptors, Immunologic, Tumor Necrosis Factor-alpha, Inflammatory Bowel Diseases, Dextran Sulfate, Mice, Knockout, ATP Binding Cassette Transporter, Subfamily B, Member 1, Toll-Like Receptor 4, Mice
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