Acyloxyacyl Hydrolase: Studies on Its Regulation and Function in Mus Musculus

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Title: Acyloxyacyl Hydrolase: Studies on Its Regulation and Function in Mus Musculus
Author: Lu, Mingfang
Abstract: Acyloxyacyl hydrolase (AOAH ) is an enzyme that detoxifies Gram -negative bacterial lipopolysaccharides (LPS ) by selectively removing secondary acyl chains from the lipid A moiety . Originally found in neutrophils , it is also produced by monocyte -macrophages and renal proximal tubule cells . In the studies described here , I found that both immature dendritic cells (DCs ) of the XS52 cell line and bone marrow -derived DCs produce AOAH . AOAH expression decreased when DCs were incubated with IL -4 , IL -1ᬠTNFa and an agonistic CD40 antibody (maturation cocktail ) , and increased following treatment with microbial agonists that engage 3 distinct Toll -like receptors (LPS , TLR4 ; CpG oligodeoxynucleotides , TLR9 ; and a Gram -positive bacterium (Micrococcus luteus ) , TLR2 ) . Maturation cocktail treatment also diminished , while LPS treatment enhanced or maintained , the cells' ability to kill E . coli , deacylate LPS , and degrade bacterial proteins . Enzymatic deacylation of LPS is thus an intrinsic , regulated mechanism by which DCs may modulate host responses to this potent bacterial agonist . To study the biological functions of AOAH , AOAH -deficient mice were generated by targeted gene disruption . AOAH did not protect mice from lethal doses of LPS or Gram -negative bacterial challenge . In response to subcutaneous injections of LPS , however , AOAH -deficient mice produced significantly higher levels of non -specific (polyclonal ) IgM and IgG3 than did wild type mice . Anti -double -stranded DNA and anti -nucleosome IgM and IgG antibody levels were also higher in LPS -immunized AOAH -deficient mice than in wild type control mice . In addition , the partially -deacylated LPS product (dLPS ) induced lower polyclonal antibody responses in vivo than did mock -treated LPS , yet the anti -LPS specific responses to dLPS and LPS were equivalent . These results suggest that AOAH may diminish potentially harmful polyclonal antibody responses to Gram -negative infection but maintain the protective anti -LPS specific response . Since B cells do not produce the enzyme , my results also point to an important role for macrophages and DCs in modulating B -cell responses to LPS antigens . In addition , the absence of AOAH did not alter the ability of LPS to function as an adjuvant , indicating that this activity is mechanistically distinct from stimulation of polyclonal antibody production . Finally , the ability of a bacterial lipopeptide to stimulate polyclonal antibody production only in AOAH - / - mice suggests that the enzyme may also regulate immune responses to non -LPS bacterial agonists .
URI: http : / /hdl .handle .net /2152 .5 /393
Date: 2004-01-14

Citation

Acyloxyacyl Hydrolase: Studies on Its Regulation and Function in Mus Musculus. Graduate School of Biomedical Sciences. Available electronically from http : / /hdl .handle .net /2152 .5 /393 .

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