Linked Life Data

17878357

Source:http://linkedlifedata.com/resource/pubmed/id/17878357

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
7
pubmed:dateCreated
2007-9-19
pubmed:abstractText
In innate immunity, microbial components stimulate macrophages to produce antimicrobial substances, cytokines, other proinflammatory mediators, and IFNs via TLRs, which trigger signaling pathways activating NF-kappaB, MAPKs, and IFN response factors. We show in this study that, in contrast to its activating role in T cells, in macrophages the protein phosphatase calcineurin negatively regulates NF-kappaB, MAPKs, and IFN response factor activation by inhibiting the TLR-mediated signaling pathways. Evidence for this novel role for calcineurin was provided by the findings that these signaling pathways are activated when calcineurin is inhibited either by the inhibitors cyclosporin A or FK506 or by small interfering RNA-targeting calcineurin, and that activation of these pathways by TLR ligands is inhibited by the overexpression of a constitutively active form of calcineurin. We further found that IkappaB-alpha degradation, MAPK activation, and TNF-alpha production by FK506 were reduced in macrophages from mice deficient in MyD88, Toll/IL-1R domain-containing adaptor-inducing IFN-beta (TRIF), TLR2, or TLR4, whereas macrophages from TLR3-deficient or TLR9 mutant mice showed the same responses to FK506 as those of wild-type cells. Biochemical studies indicate that calcineurin interacts with MyD88, TRIF, TLR2, and TLR4, but not with TLR3 or TLR9. Collectively, these results suggest that calcineurin negatively regulates TLR-mediated activation pathways in macrophages by inhibiting the adaptor proteins MyD88 and TRIF, and a subset of TLRs.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
AIM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/Adaptor Proteins, Vesicular..., http://linkedlifedata.com/resource/pubmed/chemical/Calcineurin, http://linkedlifedata.com/resource/pubmed/chemical/I-kappa B Kinase, http://linkedlifedata.com/resource/pubmed/chemical/Interferon Regulatory Factor-3, http://linkedlifedata.com/resource/pubmed/chemical/Interferon-beta, http://linkedlifedata.com/resource/pubmed/chemical/Myeloid Differentiation Factor 88, http://linkedlifedata.com/resource/pubmed/chemical/NF-kappa B, http://linkedlifedata.com/resource/pubmed/chemical/RNA, Small Interfering, http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Tumor Necrosis Factor, http://linkedlifedata.com/resource/pubmed/chemical/TICAM-1 protein, mouse, http://linkedlifedata.com/resource/pubmed/chemical/Toll-Like Receptors
pubmed:status
MEDLINE
pubmed:month
Oct
pubmed:issn
0022-1767
pubmed:author
pubmed:issnType
Print
pubmed:day
1
pubmed:volume
179
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
4598-607
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed:year
2007
pubmed:articleTitle
Calcineurin negatively regulates TLR-mediated activation pathways.
pubmed:affiliation
Department of Biological Sciences, Stanford University, Stanford, CA 94305, USA. ykang@scripps.edu
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't