Activity of monosaccharide lipid A analogues in human monocytic cells as agonists or antagonists of bacterial lipopolysaccharide.
The lipid A portion of bacterial lipopolysaccharide (LPS) plays a central role in the production of endotoxic mediators. Different responses between human and murine macrophages to lipid A-like structures have been indicated. We investigated a series of structurally related monosaccharide lipid A analogues for their potency to activate human macrophage U937 cells and peripheral blood mononuclear cells for production of tumor necrosis factor-alpha and interleukin-6 compared with their potency to activate murine macrophage RAW264.7 cells. Two of the analogues were found to have sufficient potency to activate the human cells as well as the murine cells. These analogues comprise D-glucosamine, phosphoryl groups, and acyl groups of defined carbon chain lengths (C(14) and C(12)) in a ratio of 1:1:3. This ratio of molecular constituents is proportional to that of the complete disaccharide structure of lipid A (2:2:6). Other analogues with two or four C(14) acyl groups and with three acyl groups but including a C(10) or a C(16) acyl group, which are active to murine cells, showed no LPS-agonistic activity, but did show LPS-antagonistic activity, to human cells. An LPS-antagonistic analogue in the murine cells also showed antagonistic activity in human cells. These results reveal that lipid A analogues recognized as being LPS agonists by human macrophages have common structural features in monosaccharide and disaccharide structures which are more strict than those required for recognition by murine macrophages and that broad lipid A-like structures are recognized as being LPS antagonists by human cells but are recognized by murine cells as being either LPS agonists or antagonists.
Matsuura
M
M
Department of Microbiology, Jichi Medical School, Tochigi 329-0498, Japan. mmatsuur@jichi.ac.jp
Kiso
M
M
Hasegawa
A
A
D000818:Animals; D002460:Cell Line; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008050:Lipid A / Q000031:analogs & derivatives* / Q000737:chemistry / Q000276:immunology*; D008070:Lipopolysaccharides / Q000819:agonists / Q000037:antagonists & inhibitors / Q000276:immunology*; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D020298:U937 Cells
D015850:Interleukin-6; D008050:Lipid A; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha