2005
DOI: 10.4049/jimmunol.175.7.4669
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Molecular Basis of Reduced Potency of Underacylated Endotoxins

Abstract: Potent TLR4-dependent cell activation by Gram-negative bacterial endotoxins depends on sequential endotoxin-protein and protein-protein interactions with LPS-binding protein, CD14, myeloid differentiation protein 2 (MD-2), and TLR4. Previous studies have suggested that reduced agonist potency of underacylated endotoxins (i.e., tetra- or penta- vs hexa-acylated) is determined by post-CD14 interactions. To better define the molecular basis of the differences in agonist potency of endotoxins differing in fatty ac… Show more

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Cited by 140 publications
(159 citation statements)
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“…The differences in potency we observed between LOS wt and LOS msbB in inducing airway inflammatory responses in vivo were strikingly similar to differences previously observed in LBP-dependent in vitro activation by these LOS species of cells expressing mCD14, MD-2, and TLR4 (17). Our findings thus strongly suggest that the molecular requirements for airway responsiveness to endotoxin correspond closely to the require- Figure 4.…”
Section: Discussionsupporting
confidence: 73%
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“…The differences in potency we observed between LOS wt and LOS msbB in inducing airway inflammatory responses in vivo were strikingly similar to differences previously observed in LBP-dependent in vitro activation by these LOS species of cells expressing mCD14, MD-2, and TLR4 (17). Our findings thus strongly suggest that the molecular requirements for airway responsiveness to endotoxin correspond closely to the require- Figure 4.…”
Section: Discussionsupporting
confidence: 73%
“…MD-2-null mice do not mobilize airway inflammatory responses to nasally instilled LOS aggregates but are responsive to purified monomeric LOS:MD-2 (unpublished observation), confirming that the loss of responsiveness of MD-2-null mice to endotoxin is due to the absence of MD-2. In vitro, differences in potency of hexaacylated versus underacylated endotoxin species in inducing TLR4-dependent cell activation reflect differences in the functional properties of endotoxin bound to MD-2 (17,19). Thus, the differences we observed in this study in the ability of LOS wt versus LOS msbB to induce airway inflammation most likely reflect differences in the functional properties of hexacylated versus pentacylated LOS bound to MD-2 in the airway.…”
Section: Discussionmentioning
confidence: 37%
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