title: The significance of the hydrophilic backbone and the hydrophobic fatty acid regions of lipid A for macrophage binding and cytokine induction.
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 and to induce cytokine-release in J774.1 cells. LPS, synthetic Escherichia coli-type lipid A (compound 506) and tetraacyl precursor Ia (compound 406) inhibited the binding of 125I-LPS to macrophage-like J774.1 cells and induced the release of tumor necrosis factor alpha (TNF alpha) 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 (alpha-phosphonooxyethyl analogue of 406) > 406 >> 404 (4'-monophosphoryl partial structure of 406) > 405 (1-monophosphoryl partial structure of 406). In the case of hexaacyl preparations, compounds 506, PE-1 (alpha-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 beta-phosphonooxyethyl 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.
authors.affiliation: Forschungsinstitut Borstel, Institut für Experimentelle Biologie und Medizin, FRG.
authors.forename: T
authors.initials: T
authors.lastname: Kirikae
authors.forename: F U
authors.initials: FU
authors.lastname: Schade
authors.forename: U
authors.initials: U
authors.lastname: Zähringer
authors.forename: F
authors.initials: F
authors.lastname: Kirikae
authors.forename: H
authors.initials: H
authors.lastname: Brade
authors.forename: S
authors.initials: S
authors.lastname: Kusumoto
authors.forename: T
authors.initials: T
authors.lastname: Kusama
authors.forename: E T
authors.initials: ET
authors.lastname: Rietschel
mesh_terms: D000215:Acylation; D000818:Animals; D001667:Binding, Competitive; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism*; D004731:Endotoxins / Q000737:chemistry; D005227:Fatty Acids / Q000737:chemistry; D005786:Gene Expression Regulation / Q000187:drug effects; D006017:Glycolipids / Q000737:chemistry; D015850:Interleukin-6 / Q000378:metabolism; D008050:Lipid A / Q000031:analogs & derivatives / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D015394:Molecular Structure; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016207:Cytokines; D004731:Endotoxins; D005227:Fatty Acids; D006017:Glycolipids; D015850:Interleukin-6; D008050:Lipid A; D014409:Tumor Necrosis Factor-alpha; C040142:lipid A precursors, bacterial; C044101:endotoxin, Escherichia coli