title: Acyclic analogue of lipid A stimulates TNF-alpha and arachidonate release via a unique LPS-signaling pathway.
abstract: LPS has been implicated in the pathogenesis of Gram-negative bacterial sepsis. Despite intensive efforts to define the LPS-signal transduction pathway, CD14 is the sole molecule clearly demonstrated to possess signaling capabilities. However, it remains unclear whether CD14 is the only LPS-signaling molecule expressed in phagocytes and how CD14-mediated signaling occurs. Compound SDZ 280.961 is a synthetic triacylated amino acid that structurally resembles the reducing sugar moiety of lipid A. SDZ 280.961 effectively stimulated TNF-alpha release from human PBMC. Co-incubation of PBMC with the specific LPS inhibitor Rhodobacter sphaeroides lipid A inhibited SDZ 280.961-mediated stimulation of TNF-alpha release, indicating that this analogue signals mononuclear cells via a LPS-activated signaling pathway. Induction of TNF-alpha release from mononuclear cells by SDZ 280.961 was strongly dependent on the presence of serum and was enabled by the presence of purified LPS-binding protein, characteristics of CD14-mediated signaling. In contrast, SDZ 280.961-mediated signaling was not inhibited by blocking anti-CD14 mAbs. A Chinese hamster ovary fibroblast line transfected with human CD14, which responds to LPS in a manner qualitatively similar to that of macrophage cell lines, failed to respond to SDZ 280.961. Taken together, these data suggest that the lipid A analogue SDZ 280.961 activates monocytes via a unique LPS-signal transduction pathway that appears to be independent of CD14.
authors.affiliation: Department of Internal Medicine, Maxwell Finland Laboratory for Infectious Diseases, Boston City Hospital, Boston University School of Medicine, MA 02118.
authors.forename: M A
authors.initials: MA
authors.lastname: Fagan
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.forename: P
authors.initials: P
authors.lastname: Stütz
authors.forename: H
authors.initials: H
authors.lastname: Vyplel
authors.forename: D T
authors.initials: DT
authors.lastname: Golenbock
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D015703:Antigens, CD / Q000276:immunology; D015214:Antigens, Differentiation, Myelomonocytic / Q000276:immunology; D016718:Arachidonic Acid / Q000378:metabolism*; D002240:Carbohydrate Sequence; D002460:Cell Line; D006801:Humans; D008050:Lipid A / Q000031:analogs & derivatives* / Q000494:pharmacology; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides / Q000276:immunology*; D051379:Mice; D008969:Molecular Sequence Data; D010586:Phagocytes / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D008050:Lipid A; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; C090496:SDZ 280-961; D016718:Arachidonic Acid