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Although recognition of lipopolysaccharide (LPS) by the myeloid differentiation factor 2-Toll-like receptor 4 complex is important for triggering protective inflammatory responses in animals, terminating many of these responses requires LPS inactivation by a host lipase, acyloxyacyl hydrolase (AOAH). To test whether endogenously produced recombinant AOAH can modulate responses to LPS and gram-negative bacteria, we engineered transgenic mice that overexpress AOAH in dendritic cells and macrophages, cell types that normally produce it. Transgenic mice deacylated LPS more rapidly than did wild-type controls. They also were protected from LPS-induced hepatosplenomegaly, recovered more quickly from LPS-induced weight loss, and were more likely to survive when challenged with live Escherichia coli. Constitutive overexpression of AOAH in vivo hastened recovery from LPS exposure without interfering with the normal acute inflammatory response to this important microbial signal molecule. Our results suggest that the extent to which macrophages and dendritic cells produce AOAH may influence the outcome of many gram-negative bacterial diseases.

Original publication

DOI

10.1086/646616

Type

Journal article

Journal

J Infect Dis

Publication Date

01/12/2009

Volume

200

Pages

1685 - 1693

Keywords

Animals, Antibodies, Monoclonal, Antigens, CD, Antigens, Differentiation, Myelomonocytic, Carboxylic Ester Hydrolases, Dendritic Cells, Enzyme Induction, Gram-Negative Bacterial Infections, Hepatomegaly, Lipopolysaccharides, Liver, Macrophages, Peritoneal, Mice, Mice, Inbred C57BL, Mice, Transgenic, Promoter Regions, Genetic, RNA, Messenger, Transfection