title: Cytokine induction by purified lipoteichoic acids from various bacterial species--role of LBP, sCD14, CD14 and failure to induce IL-12 and subsequent IFN-gamma release.
abstract: We have recently shown that highly purified lipoteichoic acid (LTA) represents a major immunostimulatory principle of Staphylococcus aureus. In order to test whether this translates to other bacterial species, we extracted and purified LTA from 12 laboratory-grown species. All LTA induced the release of TNF-alpha, IL-1beta, IL-6 and IL-10 in human whole blood. Soluble CD14 (sCD14) inhibited monokine induction by LTA but failed to confer LTA responsiveness for IL-6 and IL-8 release of human umbilical vein endothelial cells (HUVEC). In a competitive LPS-binding protein (LBP) binding assay, the IC(50) of the tested LTA preparations was up to 3,230-fold higher than for LPS. LBP enhanced TNF-alpha release of human peripheral blood mononuclear cells (PBMC) upon LPS but not LTA stimulation. These data demonstrate a differential role for the serum proteins LBP and sCD14 in the recognition of LPS and LTA. Different efficacies of various anti-CD14 antibodies against LPS vs. LTA-induced cytokine release suggest that the recognition sites of CD14 for LPS and LTA are distinct with a partial overlap. While the maximal achievable monokine release in response to LTA was comparable to LPS, all LTA induced significantly less IL-12 and IFN-gamma. IL-12 substitution increased LTA-inducible IFN-gamma release up to 180-fold, suggesting a critical role of poor LTA-inducible IL-12 for IFN-gamma formation. Pretreatment with IFN-gamma rendered galactosamine-sensitized mice sensitive to challenge with LTA. In conclusion, LTA compared to LPS, are weak inducers of IL-12 and subsequent IFN-gamma formation which might explain their lower toxicity in vivo.
authors.affiliation: Biochemical Pharmacology, University of Konstanz, D-78457 Konstanz, Germany.
authors.forename: Corinna
authors.initials: C
authors.lastname: Hermann
authors.forename: Ingo
authors.initials: I
authors.lastname: Spreitzer
authors.forename: Nicolas W J
authors.initials: NW
authors.lastname: Schröder
authors.forename: Siegfried
authors.initials: S
authors.lastname: Morath
authors.forename: Martin D
authors.initials: MD
authors.lastname: Lehner
authors.forename: Werner
authors.initials: W
authors.lastname: Fischer
authors.forename: Christine
authors.initials: C
authors.lastname: Schütt
authors.forename: Ralf R
authors.initials: RR
authors.lastname: Schumann
authors.forename: Thomas
authors.initials: T
authors.lastname: Hartung
mesh_terms: D000209:Acute-Phase Proteins; D000818:Animals; D001419:Bacteria / Q000737:chemistry*; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000276:immunology; D006801:Humans; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000302:isolation & purification / Q000494:pharmacology* / Q000633:toxicity; D008297:Male; D008562:Membrane Glycoproteins; D051379:Mice; D008807:Mice, Inbred BALB C; D012995:Solubility; D013682:Teichoic Acids / Q000302:isolation & purification / Q000494:pharmacology* / Q000633:toxicity; D000099231:Lipopolysaccharide-Binding Protein
chemical_list: D000209:Acute-Phase Proteins; D002352:Carrier Proteins; D016207:Cytokines; D007371:Interferon-gamma; D018664:Interleukin-12; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D013682:Teichoic Acids; D000099231:Lipopolysaccharide-Binding Protein; C009900:lipoteichoic acid