A synthetic TLR4 antagonist has anti-inflammatory effects in two murine models of inflammatory bowel disease.
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.
Fort
Madeline M
MM
Corixa Corporation, Seattle, WA 98101, USA.
Mozaffarian
Afsaneh
A
Stöver
Axel G
AG
Correia
Jean da Silva
Jda S
Johnson
David A
DA
Crane
R Thomas
RT
Ulevitch
Richard J
RJ
Persing
David H
DH
Bielefeldt-Ohmann
Helle
H
Probst
Peter
P
Jeffery
Eric
E
Fling
Steven P
SP
Hershberg
Robert M
RM
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
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