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 r ole in the production of endotoxic mediators. Different responses between h uman and murine macrophages to lipid A-like structures hale been indicated. me investigated a series of structurally related monosaccharide lipid A an alogues for their potency to activate human macrophage U937 cells and perip heral blood mononuclear cells for production of tumor necrosis factor-alpha and interleukin-6 compared with their potency to activate murine macrophag e RAW264.7 cells. Two of the analogues were found to have sufficient potenc y to activate the human tells as Hell as the murine cells. These analogues comprise D-glucosamine, phosphoryl groups, and acyl groups of defined carbo n chain lengths (C-14 and C-12) in a ratio of 1:1:3. This ratio of molecula r constituents is proportional to that of the complete disaccharide structu re of lipid A (2:2:6). Other analogues with two or four C-14 acyl groups an d with three acyl groups but including a C-10 or a C-16 acyl group, which a re active to murine cells, showed no LPS-agonistic activity, but did show L PS-antagonistic activity to human cells. An LPS-antagonistic analogue in th e murine cells also showed antagonistic activity in human cells. These resu lts reveal that lipid A analogues recognized as being LPS agonists have hum an macrophages have common structural features in monosaccharide and disacc haride structures which are more strict than those required far recognition by murine macrophages and that broad lipid A-like structures are recognize d as being LPS antagonists by human cells but are recognized by murine cell s as being either LPS agonists or antagonists.