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The significance of the hydrophilic backbone and the hydrophobic fatty acid regions of lipid a for macrophage binding and cytokine induction
Authors:Teruo Kirkiae  FUlrich Schade  Ulrich Zähringer  Fumiko Kirikae  Helmut Brade  Shoichi Kusomoto  Tsuneo Kusama  Ernst Th Rietschel
Institution:Forschungsinstitut Borstel, Institut für Experimentelle Biologie und Medizin, D-23845 Borstel, FRG;Faculty of Science, Osaka University, Osaka, Japan;Research Institute, Daiichi Pharmaceutical Co. Ltd., Tokyo, Japan
Abstract:Abstract Natural partial structures of lipopolysaccharide (LPS) as well as synthetic analogues and derivatives of lipid A were compared with respect to inhibit the binding of 125I-labelled Re-chemotype LPS to mouse macrophage-like J774.1 cells to induce cytokine-release in J774.1 cells. LPS, synthetic Escherichia coli -type lipid A (compound 506) and tetraacyl percursor Ia (compound 406) inhibited the binding of 125I-LPS to macrophage-like J774.1 cells and induced the release of tumor ncerosis factor α (TNFα) and interleukin 6 (IL-6). Deacylated R-chemotype LPS preparations were completely inactive in inhibiting binding and in inducing cytokine-release. Among tetraacyl compounds, the inhibition-capacity of LPS-binding was in decreasing order: PE-4 ( α -phosphonooxyethyl analogue of 406)>406⪢>404(4′-monophosphoryl partial structure of 406)>405 (1-monophosphoryl partial structure of 406). In the case of hexaccyl preparations, compounds 506, PE-1 (α-phosphonooxyethyl analogue of 506) and PE-2 (differing from PE-1 in having 14:0 at positions 2 and 3 of the reducing GlcN) inhibited LPS-binding and induced cytokine release equally well, whereas preparation PE-3 (differing from PE-2 in containing a β-phosphhonooxyethyl group) showed a substantially lower capacity in binding-inhibition and cytokine-induction. The conclusion is that chemical changes in the hydrophilic lipid A backbone reduce the capacity of lipid A to bind to cells, whereas the number of fatty acids determines the capacity of lipid A to activate cells. These results indicate that the bisphosphorylated hexosamine backbone of lipid A is essential for specific binding of LPS to macrophages and that the acylation pattern plays a critical role for LPS-promoted cell activation, i.e. cytokine induction.
Keywords:Lipopolysaccharide  Lipopolyusaccharide receptor  Synthetic lipid A  Macrophage-like cell line
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