Plasma constituents regulate LPS binding to, and release from, the monocyte cell surface

Innate immunity to Gram-negative bacteria involves regulated mechanisms tha t allow sensitive but limited responses to LPS. Two important pathways that lead to host cell activation and LPS deactivation involve: (i) LPS interac tions with CD14 and Toil-like receptor 4 on cells (activation), and (ii) LP S sequestration by plasma lipoproteins (deactivation). Whereas these pathwa ys were previously thought to be independent and essentially irreversible, we found that they are connected by a third pathway: (iii) the movement of LPS from host cells to plasma lipoproteins. Our data show that, in the pres ence of human plasma, LPS binds transiently to monocyte surfaces and then m oves from the cell surface to plasma lipoproteins. Soluble CD14 enhances LP S release from cells in the presence of lipoproteins, whereas LPS binding p rotein and phospholipid transfer protein do not, The transfer of cell-bound LPS to lipoproteins is accompanied by reduced cell responses to the LPS. s uggesting that the movement of LPS from leukocytes into lipoproteins may at tenuate host responses to LPS in vivo. Preliminary data suggest that change s that occur in the plasma after trauma or during sepsis decrease LPS bindi ng to leukocytes while greatly increasing the rate of LPS release from cell s.