Abstract
Sepsis and septic shock are clinical conditions resulting from infections, mediated through a complex interplay of mediators and receptors. It is known that lipopolysaccharide (LPS) is primarily responsible for stimulating cells of the immune system including monocytes and macrophages play a pivotal role in immune modulation. Monophosphoryl lipid A (MPL), a modified form of LPS, has been shown to exert immunomodulatory effects similar to LPS, but relatively non-toxic. The present study was designed to compare the immunomodulatory effects of LPS and MPL on human monocytes in vitro. In addition, the development of tolerance in vitro by various agents or in vivo in sepsis and septic shock has been examined. Results show that MPL stimulates monocytes to release equal amounts of superoxide (O2) and higher amounts of hydrogen peroxide (H2O2) compared to LPS whereas MPL- pretreated and challenged monocytes showed greater hyporesponsiveness in releasing these radicals than that seen by LPS. Data suggest that MPL stimulates monocytes via similar but limited pathways than LPS, and O2. and H2O2 release in LPS- and MPL-stimulated monocytes are regulated differently. MPL-stimulated monocytes are found to release nitric oxide (NO) through a novel mechanism that has yet to be determined. MPL-stimulated cells release lower levels of cytokines compared to that released by LPS. Variable degrees of phagocytosis-related activities and receptor expression are observed in LPS- and MPL-stimulated monocytes, suggesting the existence of a time-and dose-dependent "compensatory" mechanism. Both LPS and staphylococcal enterotoxin B (SEB) can induce tolerance in vitro to specific antigens or non-specific stimuli, indicating the existence of cross-tolerization. Sepsis and septic shock are found to induce hyporesponsiveness in vivo to O2 and cytokine release in response to different activating stimuli in vitro, suggesting a generalized immune suppression in sepsis and septic shock. It is concluded that MPL is less toxic than LPS and yet is a potent immune modulator. Sepsis- and septic shock-induced tolerance that includes an attenuated reactive oxygen radical and cytokine release is a non-specific phenomenon and this tolerance may be disadvantageous for the host.