INDUCTION OF PROINFLAMMATORY RESPONSES IN HUMAN MONOCYTES BY PARTICULATE AND SOLUBLE FORMS OF LIPOPOLYSACCHARIDE

Lipopolysaccharide (LPS), a major constituent of the outer membrane of Gram-negative bacteria, is thought to be chiefly responsible for induction by these organisms of Gram-negative septic shock, an often fatal complication of Gram-negative septicemia. Accordingly, monocytes and macrophages, which are believed to be the primary cellular targets of LPS, have been shown to mount vigorous proinflammatory responses to highly purified, soluble LPS. Relatively less is known, however, about the ability of these cells to respond to native, insoluble forms of LPS, such as those represented by intact Gram-negative bacterial particles. Furthermore, the intact microbe would be expected to exhibit additional non-LPS components that are capable of stimulating proinflammatory responses, and the relative roles of these components and LPS in stimulating proinflammatory responses have not, to date, been fully defined. Therefore, experiments have been conducted to assess stimulation of human monocytes by highly purified, soluble LPS as well as by particulate forms of LPS, including Gram-negative bacterial particles and LPS-coated latex beads. As indicated by induction of procoagulant activity and production of tumor necrosis factor, LPS appears to be the Gram-negative bacterial component of primary importance for induction of monocytic proinflammatory responses. Furthermore, the presentation of LPS associated with the bacterial surface is also capable of eliciting such responses, albeit with less potency than that observed for soluble LPS. At least part of this reduction in potency appears attributable to the particulate nature of bacterium-bound LPS, since a reduction in potency is similarly observed for soluble LPS coated onto latex beads.