Linked Life Data

19430901

Source:http://linkedlifedata.com/resource/pubmed/id/19430901

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
9
pubmed:dateCreated
2009-12-16
pubmed:abstractText
The signaling pathways of mammalian Toll-like receptors (TLR) are well characterized, but the initial molecular mechanisms activated following ligand interactions with the receptors remain poorly defined. Here, we show a membrane controlling mechanism that is initiated by ligand binding to TLR-2, -3 and-4 to induce Neu1 sialidase activity within minutes in live primary bone marrow (BM) macrophage cells and macrophage and dendritic cell lines. Central to this process is that Neu1 and not Neu2,-3 and-4 forms a complex with TLR-2,-3 and-4 on the cell surface of naïve macrophage cells. Neuraminidase inhibitors BCX1827, 2-deoxy-2,3-dehydro-N-acetylneuraminic acid (DANA), zanamivir and oseltamivir carboxylate have a limited significant inhibition of the LPS-induced sialidase activity in live BMC-2 macrophage cells but Tamiflu (oseltamivir phosphate) completely blocks this activity. Tamiflu inhibits LPS-induced sialidase activity in live BMC-2 cells with an IC(50) of 1.2 microM compared to an IC(50) of 1015 microM for its hydrolytic metabolite oseltamivir carboxylate. Tamiflu blockage of LPS-induced Neu1 sialidase activity is not affected in BMC-2 cells pretreated with anticarboxylesterase agent clopidogrel. Endotoxin LPS binding to TLR4 induces Neu1 with subsequent activation of NFkappaB and the production of nitric oxide and pro-inflammatory IL-6 and TNFalpha cytokines in primary and macrophage cell lines. Hypomorphic cathepsin A mice with a secondary Neu1 deficiency respond poorly to LPS-induced pro-inflammatory cytokines compared to the wild-type or hypomorphic cathepsin A with normal Neu1 mice. Our findings establish an unprecedented mechanism for pathogen molecule-induced TLR activation and cell function, which is critically dependent on Neu1 sialidase activity associated with TLR ligand treated live primary macrophage cells and macrophage and dendritic cell lines.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Dec
pubmed:issn
1573-4986
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
26
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1197-212
pubmed:meshHeading
pubmed-meshheading:19430901-Animals, pubmed-meshheading:19430901-Bone Marrow Cells, pubmed-meshheading:19430901-Cell Membrane, pubmed-meshheading:19430901-Cell Survival, pubmed-meshheading:19430901-Cells, Cultured, pubmed-meshheading:19430901-Cytokines, pubmed-meshheading:19430901-Dendritic Cells, pubmed-meshheading:19430901-Enzyme Inhibitors, pubmed-meshheading:19430901-Humans, pubmed-meshheading:19430901-Immunoprecipitation, pubmed-meshheading:19430901-Inflammation Mediators, pubmed-meshheading:19430901-Ligands, pubmed-meshheading:19430901-Lipopolysaccharides, pubmed-meshheading:19430901-Macrophages, pubmed-meshheading:19430901-Mice, pubmed-meshheading:19430901-Neuraminidase, pubmed-meshheading:19430901-Nitric Oxide, pubmed-meshheading:19430901-Oseltamivir, pubmed-meshheading:19430901-Receptors, Pattern Recognition, pubmed-meshheading:19430901-Toll-Like Receptors
pubmed:year
2009
pubmed:articleTitle
Dependence of pathogen molecule-induced toll-like receptor activation and cell function on Neu1 sialidase.
pubmed:affiliation
Department of Microbiology & Immunology, Queen's University, Kingston, ON, K7L3N6, Canada.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't