title: Regulatory mechanisms of host responsiveness to endotoxin (lipopolysaccharide).
abstract: During Gram-negative endotoxemia, precise regulation of monocyte/macrophage (M phi) responsiveness to lipopolysaccharide (LPS) is critical to preserve host defense while avoiding complications such as organ failure and death. We will discuss regulation of LPS-M phi interactions by LPS-binding plasma proteins and by LPS-induced changes in M phi responsiveness. Upon exposure to plasma, LPS binds to either lipoproteins or LPS-binding protein (LBP; a 60-kilodalton glycoprotein with a high-affinity binding site for the lipid A moiety of rough and smooth LPS). The LPS-LBP complex stimulates the M phi by binding to its cellular receptor, CD14 (a monocyte/M phi-specific, phosphatidylinositol-anchored surface glycoprotein). Pretreatment of whole blood with anti-CD 14 monoclonal antibody reduces the responsiveness of monocytes to LPS [determined by tumor necrosis factor-alpha (TNF-alpha) release]at least 10-fold. Similarly, cellular responsiveness to LPS is diminished at least 100-fold by depletion of plasma LBP with anti-LBP antibody. Compared to LPS-LBP induction of TNF-alpha, LPS-lipoprotein complexes are as much as 10,000-fold less active. Thus, partitioning of LPS between LBP and lipoproteins markedly influences M phi responsiveness to LPS. LPS also directly induces M phi hyporesponsiveness to itself by a process known as adaptation; exposure of M phi to less than or equal to LPS/ml (subthreshold for TNF induction) for 6-9 reduces the sensitivity of the M phi to subsequent challenge up to 1,000-fold, so that 1 microgram/ml rather than 1 ng/ml of LPS is required for maximal induction of TNF-alpha.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Immunology, Research Institute of Scripps Clinic, La Jolla, Calif.
authors.forename: J
authors.initials: J
authors.lastname: Mathison
authors.forename: P
authors.initials: P
authors.lastname: Tobias
authors.forename: E
authors.initials: E
authors.lastname: Wolfson
authors.forename: R
authors.initials: R
authors.lastname: Ulevitch
mesh_terms: D000209:Acute-Phase Proteins; D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D004731:Endotoxins / Q000633:toxicity*; D008070:Lipopolysaccharides / Q000378:metabolism / Q000633:toxicity; D008264:Macrophages / Q000187:drug effects / Q000502:physiology; D008562:Membrane Glycoproteins; D014115:Toxemia / Q000209:etiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D000099231:Lipopolysaccharide-Binding Protein
chemical_list: D000209:Acute-Phase Proteins; D001798:Blood Proteins; D002352:Carrier Proteins; D004731:Endotoxins; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D014409:Tumor Necrosis Factor-alpha; D000099231:Lipopolysaccharide-Binding Protein