Overproduction of acyloxyacyl hydrolase by macrophages and dendritic cells prevents prolonged reactions to bacterial lipopolysaccharide in vivo.
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.
Department of Internal Medicine, University of Texas Southwestern Medical School, Dallas, TX, USA.
Noredia
N
Ojogun
Tang-Yong
TY
Kuang
Baomei
B
Shao
David R
DR
Greaves
Robert S
RS
Munford
Alan W
AW
Varley
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics; D015214:Antigens, Differentiation, Myelomonocytic / Q000096:biosynthesis / Q000235:genetics; D002265:Carboxylic Ester Hydrolases / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000201:enzymology* / Q000276:immunology; D004790:Enzyme Induction / Q000187:drug effects; D016905:Gram-Negative Bacterial Infections / Q000201:enzymology / Q000276:immunology; D006529:Hepatomegaly / Q000139:chemically induced; D008070:Lipopolysaccharides / Q000276:immunology / Q000493:pharmacokinetics / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D017737:Macrophages, Peritoneal / Q000201:enzymology* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D014162:Transfection; D000097382:CD68 Molecule
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D002265:Carboxylic Ester Hydrolases; D008070:Lipopolysaccharides; D012333:RNA, Messenger; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C081026:CD68 protein, mouse; C048964:acyloxyacyl hydrolase