title: Comparison of the immunostimulatory and proinflammatory activities of candidate Gram-positive endotoxins, lipoteichoic acid, peptidoglycan, and lipopeptides, in murine and human cells.
abstract: The role of lipopolysaccharide (LPS) in the pathogenesis of Gram-negative septic shock is well established. The corresponding proinflammatory and immunostimulatory molecule(s) on the Gram-positive bacteria is less well understood, and its identification and characterization would be a key prerequisite in designing specific sequestrants of the Gram-positive endotoxin(s). We report in this paper the comparison of NF-kappaB-, cytokine- and chemokine-inducing activities of the TLR2 ligands, lipoteichoic acid (LTA), peptidoglycan (PGN), and lipopeptides, to LPS, a prototype TLR4 agonist, in murine macrophage cell-lines as well as in human blood. In murine cells, di- and triacyl liopopeptides are equipotent in their NF-kappaB inducing activity relative to LPS, but elicit much lower proinflammatory cytokines. However, both LPS and the lipopeptides potently induce the secretion of a pattern of chemokines that is suggestive of the engagement of a TLR4-independent TRIF pathway. In human blood, although the lipopeptides induce p38 MAP kinase phosphorylation and CD11b upregulation in granulocytes at ng/ml concentrations, they do not elicit proinflammatory cytokine production even at very high doses; LTA, however, activates neutrophils and induces cytokine secretion, although its potency is considerably lower than that of LPS, presumably due to its binding to plasma proteins. We conclude that, in human blood, the pattern of immunostimulation and proinflammatory mediator production elicited by LTA parallels that of LPS.
authors.affiliation: Department of Medicinal Chemistry, University of Kansas, United States.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Kimbrell
authors.forename: Hemamali
authors.initials: H
authors.lastname: Warshakoon
authors.forename: Jens R
authors.initials: JR
authors.lastname: Cromer
authors.forename: Subbalakshmi
authors.initials: S
authors.lastname: Malladi
authors.forename: Jennifer D
authors.initials: JD
authors.lastname: Hood
authors.forename: Rajalakshmi
authors.initials: R
authors.lastname: Balakrishna
authors.forename: Tandace A
authors.initials: TA
authors.lastname: Scholdberg
authors.forename: Sunil A
authors.initials: SA
authors.lastname: David
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D001773:Blood Cells / Q000187:drug effects; D002460:Cell Line; D002477:Cells / Q000187:drug effects*; D004731:Endotoxins / Q000276:immunology / Q000494:pharmacology*; D006094:Gram-Positive Bacteria / Q000737:chemistry; D006801:Humans; D007249:Inflammation / Q000139:chemically induced* / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology*; D008074:Lipoproteins / Q000276:immunology / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D051379:Mice; D010457:Peptidoglycan / Q000276:immunology / Q000494:pharmacology*; D013682:Teichoic Acids / Q000276:immunology / Q000494:pharmacology*; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000097:blood / Q000378:metabolism
chemical_list: D000276:Adjuvants, Immunologic; D004731:Endotoxins; D008070:Lipopolysaccharides; D008074:Lipoproteins; D010457:Peptidoglycan; D013682:Teichoic Acids; D051195:Toll-Like Receptor 2; C009900:lipoteichoic acid