Original Literature | Model OverView |
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Publication
Title
Gram-negative endotoxin: an extraordinary lipid with profound effects oneukaryotic signal transduction.
Affiliation
Department of Biochemistry, Merck Sharp and Dohme Research Laboratories, Rahway,New Jersey 07065.
Abstract
The lipid A domain of lipopolysaccharide (LPS) is a unique, glucosamine-basedphospholipid that makes up the outer monolayer of the outer membrane of mostgram-negative bacteria. Because of its profound pharmacological effects onanimal cells, especially those of the immune system, lipid A is also known asendotoxin. Despite decades of earlier work, the precise chemistry of endotoxinsand the biochemical pathways for their enzymatic synthesis have been elucidatedonly within the past 5 years. In this review, we summarize the essentials ofendotoxin biochemistry and also present recent experiments aimed at identifyingsurface receptors, signal-transducing elements, transcriptional factors, and keyintracellular targets involved in the response of animal cells to endotoxins.
PMID
1916089
|
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PMID: 1916089, 2471708 The binding specificity of LBP for LPS is for the lipid A moiety. Accordingly, LBP binds to LPS isolated from rough and smooth forms of bacteria.
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PMID: 1916089, 3399892 OTF-2 levels increase slowly after LPS treatment, and its augmentation represents an increase in the steady-state level of the mRNA that encodes it. PMID: 1916089 Transforming growth factor-fl specifically prevents the increase in steady-state levels of OTF-2 protein and mRNA normally observed after LPS treatment of 70Z/3 cells.
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PMID: 1916089, 6322127 There is a 30- to 50-fold increase in kappa transcription.
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PMID: 1916089 Normal cells show huge increases in the level of nuclear NF-KB minutes after LPS treatment.
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PMID: 1916089 Transforming growth factor-fl specifically prevents the increase in steady-state levels of OTF-2 protein and mRNA normally observed after LPS treatment of 70Z/3 cells.
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PMID: 1916089 LPS may accelerate the internalization of TNF-R faster than TNF-R can be replaced.
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PMID: 1916089, 3096580 The activation of NF-xB from the cytoplasm can be mimicked by treatment of the cells with phorbol 12-myristate 13-acetate.
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PMID: 1916089,3537192 CD18 molecules bind particulate LPS when presented on the surface of bacteria or LPS-coated erythrocytes.
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PMID: 1916089, 1852209 The acetylated LDL (scavenger) receptors, recently cloned, are capable of binding lipid A.
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PMID: 1916089, 1698311 Moreover, antibodies against CD18 do not prevent synthesis of TNF by normal monocytes in response to LPS. PMID: 1916089 In studies with primary cultures of rabbit peritoneal exudate macrophages (PEM) or with vitamin D3-differentiated THP-1 cells, it was found that LBP-LPS complexes were as much as 1000-fold more active than LPS alone in induction of monokines such as TNF or IL 1beta.
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PMID: 1916089, 1698311 Moreover, antibodies against CD18 do not prevent synthesis of TNF by normal monocytes in response to LPS.
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PMID: 1916089 In studies with primary cultures of rabbit peritoneal exudate macrophages (PEM) or with vitamin D3-differentiated THP-1 cells, it was found that LBP-LPS complexes were as much as 1000-fold more active than LPS alone in induction of monokines such as TNF or IL 1beta.
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PMID: 1916089 When CDI4 was purified from detergent lysates of macrophages by absorption onto surfaces coated with this antibody, the CD14-coated surfaces retained the ability to bind LPS-LBP complexes, indicating that purified CD14 is sufficient for binding of LPS-LBP complexes. PMID: 1916089, 1698311 Surface-bound antibodies against CDI4, but not antibodies against other antigens, down-modulated the binding of erythrocytes coated with LPS-LBP complexes to macrophages.
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PMID: 1916089 The ligated CD14 may then directly trigger the synthesis of TNF.
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PMID: 1916089, 3129195 The NF-xB is found in almost all cells as an inactive complex, held in the cytoplasm by an inhibitor, IxB. After treatment of the cells with LPS, NF-xB activation is extremely rapid.
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