title: 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.
authors.affiliation: Corixa Corporation, Seattle, WA 98101, USA.
authors.forename: Madeline M
authors.initials: MM
authors.lastname: Fort
authors.forename: Afsaneh
authors.initials: A
authors.lastname: Mozaffarian
authors.forename: Axel G
authors.initials: AG
authors.lastname: Stöver
authors.forename: Jean da Silva
authors.initials: Jda S
authors.lastname: Correia
authors.forename: David A
authors.initials: DA
authors.lastname: Johnson
authors.forename: R Thomas
authors.initials: RT
authors.lastname: Crane
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Ulevitch
authors.forename: David H
authors.initials: DH
authors.lastname: Persing
authors.forename: Helle
authors.initials: H
authors.lastname: Bielefeldt-Ohmann
authors.forename: Peter
authors.initials: P
authors.lastname: Probst
authors.forename: Eric
authors.initials: E
authors.lastname: Jeffery
authors.forename: Steven P
authors.initials: SP
authors.lastname: Fling
authors.forename: Robert M
authors.initials: RM
authors.lastname: Hershberg
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000172:deficiency / Q000235:genetics; D000276:Adjuvants, Immunologic / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002208:Caproates / Q000737:chemistry; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D005260:Female; D005944:Glucosamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics / Q000276:immunology / Q000473:pathology* / Q000517:prevention & control*; D008050:Lipid A / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000276:Adjuvants, Immunologic; D000894:Anti-Inflammatory Agents, Non-Steroidal; C501717:CRX-526; D002208:Caproates; D008050:Lipid A; D008070:Lipopolysaccharides; D011971:Receptors, Immunologic; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D016264:Dextran Sulfate; D005944:Glucosamine