Linked Life Data

21540455

Source:http://linkedlifedata.com/resource/pubmed/id/21540455

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
171
pubmed:dateCreated
2011-5-4
pubmed:abstractText
Monophosphoryl lipid A (MLA), a nontoxic derivative of the endotoxin lipopolysaccharide (LPS), has been approved in the United States for use as a vaccine adjuvant. LPS and MLA are ligands of Toll-like receptor 4 (TLR4), and it has been unclear why LPS triggers toxic inflammation, whereas MLA generates safe and effective immunostimulation. Signaling downstream of TLR4 is mediated by the adaptor proteins TRIF [Toll-interleukin-1 (IL-1) receptor (TIR) domain-containing adaptor-inducing interferon-?], which is required for adaptive immune outcomes, and MyD88 (myeloid differentiation marker 88), which is responsible for many proinflammatory effects. Two models have provided nonexclusive explanations for the differential effects of LPS and MLA. According to the first model, MLA fails to induce maturation of the proinflammatory cytokine IL-1? because it fails to activate caspase-1, which is required for the conversion of pro-IL-1? into its bioactive form. The second model suggests that MLA triggers unequal engagement of both of the signaling adaptor pathways of TLR4, such that signaling mediated by TRIF is largely intact, whereas signaling mediated by MyD88 is incomplete. We show that the TRIF-biased signaling that is characteristic of low-toxicity MLA explains its failure to activate caspase-1. Defective induction of NLRP3, which depends on MyD88, led to decreased assembly of components of the IL-1?-activating inflammasome required for the activation of preformed, inactive procaspase-1. In addition, we elucidated the contributions of MyD88 and TRIF to priming of the NLRP3 inflammasome and demonstrated that TRIF-biased TLR4 activation by MLA was responsible for the defective production of mature IL-1?.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/Adaptor Proteins, Vesicular..., http://linkedlifedata.com/resource/pubmed/chemical/Adjuvants, Immunologic, http://linkedlifedata.com/resource/pubmed/chemical/CIAS1 protein, mouse, http://linkedlifedata.com/resource/pubmed/chemical/Carrier Proteins, http://linkedlifedata.com/resource/pubmed/chemical/Caspase 1, http://linkedlifedata.com/resource/pubmed/chemical/Inflammasomes, http://linkedlifedata.com/resource/pubmed/chemical/Interleukin-1beta, http://linkedlifedata.com/resource/pubmed/chemical/Lipid A, http://linkedlifedata.com/resource/pubmed/chemical/Myd88 protein, mouse, http://linkedlifedata.com/resource/pubmed/chemical/Myeloid Differentiation Factor 88, http://linkedlifedata.com/resource/pubmed/chemical/TICAM-1 protein, mouse, http://linkedlifedata.com/resource/pubmed/chemical/Tlr4 protein, mouse, http://linkedlifedata.com/resource/pubmed/chemical/Toll-Like Receptor 4, http://linkedlifedata.com/resource/pubmed/chemical/monophosphoryl lipid A
pubmed:status
MEDLINE
pubmed:issn
1937-9145
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
4
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
ra28
pubmed:meshHeading
pubmed:year
2011
pubmed:articleTitle
Mechanism of impaired NLRP3 inflammasome priming by monophosphoryl lipid A.
pubmed:affiliation
Department of Microbiology and Immunology and Institute for Cellular Therapeutics, University of Louisville School of Medicine, 570 South Preston Street, Louisville, KY 40202, USA.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural