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Limited By:	Author = MCGETTRICK-DILLON, ANNE;

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Displaying Results 1 - 5 of 5 on page 1 of 1

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How metabolism generates signals during innate immunity and inflammation (2013)

MCGETTRICK-DILLON, ANNE; O'NEILL, LUKE

How metabolism generates signals during innate immunity and inflammation (2013)

MCGETTRICK-DILLON, ANNE; O'NEILL, LUKE

Abstract:

The interplay between immunity, inflammation, and metabolic changes is a growing field of research. Toll-like receptors and NOD-like receptors are families of innate immune receptors, and their role in the human immune response is well documented. Exciting new evidence is emerging with regard to their role in the regulation of metabolism and the activation of inflammatory pathways during the progression of metabolic disorders such as type 2 diabetes and atherosclerosis. The proinflammatory cytokine IL-1? appears to play a central role in these disorders. There is also evidence that metabolites such as NAD+ (acting via deacetylases such as SIRT1 and SIRT2) and succinate (which regulates hypoxia-inducible factor 1?) are signals that regulate innate immunity. In addition, the extracellular overproduction of metabolites such as uric acid and cholesterol crystals acts as a signal sensed by NLRP3, leading to the production of IL-1?. These observations cast new light on the role of metabol...

http://hdl.handle.net/2262/72337

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Succinate is an inflammatory signal that induces IL-1 beta through HIF-1 alpha (2013)

MCGETTRICK-DILLON, ANNE; CORR, SINEAD; PALSSON, EVA; KELLY, VINCENT; O'NEILL, LUKE

Succinate is an inflammatory signal that induces IL-1 beta through HIF-1 alpha (2013)

MCGETTRICK-DILLON, ANNE; CORR, SINEAD; PALSSON, EVA; KELLY, VINCENT; O'NEILL, LUKE

Abstract:

Macrophages activated by the Gram-negative bacterial product lipopolysaccharide switch their core metabolism from oxidative phosphorylation to glycolysis. Here we show that inhibition of glycolysis with 2-deoxyglucose suppresses lipopolysaccharide-induced interleukin-1? but not tumour-necrosis factor-? in mouse macrophages. A comprehensive metabolic map of lipopolysaccharide-activated macrophages shows upregulation of glycolytic and downregulation of mitochondrial genes, which correlates directly with the expression profiles of altered metabolites. Lipopolysaccharide strongly increases the levels of the tricarboxylic-acid cycle intermediate succinate. Glutamine-dependent anerplerosis is the principal source of succinate, although the 'GABA (?-aminobutyric acid) shunt' pathway also has a role. Lipopolysaccharide-induced succinate stabilizes hypoxia-inducible factor-1?, an effect that is inhibited by 2-deoxyglucose, with interleukin-1? as an important target. Lipopolysacchar...

http://hdl.handle.net/2262/72421

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The myristoylation of TRIF-related adaptor molecule is essential for Toll-like receptor 4 signal transduction (2006)

MCGETTRICK-DILLON, ANNE; O'NEILL, LUKE ANTHONY JOHN

The myristoylation of TRIF-related adaptor molecule is essential for Toll-like receptor 4 signal transduction (2006)

MCGETTRICK-DILLON, ANNE; O'NEILL, LUKE ANTHONY JOHN

Abstract:

peer-reviewed
TRIF-related adaptor molecule (TRAM) is the fourth Toll/IL-1 resistance domain-containing adaptor to be described that participates in Toll-like receptor (TLR) signaling. TRAM functions exclusively in the TLR4 pathway. Here we show by confocal microscopy that TRAM is localized in the plasma membrane and the Golgi apparatus, where it colocalizes with TLR4. Membrane localization of TRAM is the result of myristoylation because mutation of a predicted myristoylation site in TRAM (TRAM-G2A) brought about dissociation of TRAM from the membrane and its relocation to the cytosol. Further, TRAM, but not TRAM-G2A, was radiolabeled with [3H]myristate in vivo. Unlike wild-type TRAM, overexpression of TRAM-G2A failed to elicit either IFN regulatory factor 3 or NF-kappaB signaling. Moreover, TRAM-G2A was unable to reconstitute LPS responses in bone marrow-derived macrophages from TRAM-deficient mice. These observations provide clear evidence that the myristoylation of TRAM targe...

http://hdl.handle.net/2262/33444

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Transcriptional regulation of the human TRIF (TIR domain-containing adaptor protein inducing interferon beta) gene. (2004)

MCGETTRICK-DILLON, ANNE; O'NEILL, LUKE ANTHONY JOHN

Transcriptional regulation of the human TRIF (TIR domain-containing adaptor protein inducing interferon beta) gene. (2004)

MCGETTRICK-DILLON, ANNE; O'NEILL, LUKE ANTHONY JOHN

Abstract:

peer-reviewed
TRIF [TIR (Toll/interleukin-1 receptor) domain-containing adaptor protein inducing interferon beta; also known as TICAM-1 (TIR-containing adaptor molecule-1)] is a key adaptor for TLR3 (Toll-like receptor 3)- and TLR4-mediated signalling. We have performed a detailed annotation of the human TRIF gene and fine analysis of the basal and inducible promoter elements lying 5' to the site of initiation of transcription. Human TRIF maps to chromosome 19p13.3 and is flanked upstream by TIP47, which encodes the mannose 6-phosphate receptor binding protein, and downstream by a gene encoding FEM1a, a human homologue of the Caenorhabditis elegans Feminisation-1 gene. Using promoter-reporter deletion constructs, we identified a distal region with the ability to negatively regulate basal transcription and a proximal region containing an Sp1 (stimulating protein 1) site that confers approx. 75% of basal transcriptional activity. TRIF expression can be induced by multiple sti...

http://hdl.handle.net/2262/33690

Marked Mark

MCGETTRICK-DILLON, ANNE; O'NEILL, LUKE ANTHONY JOHN; PALSSON, EVA

Abstract:

peer-reviewed
PKC? has been shown to play a key role in the effect of the Gram-negative bacterial product LPS; however, the target for PKC? in LPS signaling is unknown. LPS signaling is mediated by Toll-like receptor 4, which uses four adapter proteins, MyD88, MyD88 adapter-like (Mal), Toll/IL-1R domain-containing adapter inducing IFN-? (Trif), and Trif-related adapter molecule (TRAM). Here we show that TRAM is transiently phosphorylated by PKC? on serine-16 in an LPS-dependent manner. Activation of IFN regulatory factor 3 and induction of the chemokine RANTES, which are both TRAM-dependent, were attenuated in PKC?-deficient cells. TRAMS16A is inactive when overexpressed and is attenuated in its ability to reconstitute signaling in TRAM-deficient cells. We have therefore uncovered a key process in Toll-like receptor 4 signaling, identifying TRAM as the target for PKC?.

http://hdl.handle.net/2262/33442

Displaying Results 1 - 5 of 5 on page 1 of 1