Publications

Glutathione and Glutathione Transferase Omega 1 as Key Posttranslational Regulators in Macrophages

The cytoplasm of an activated macrophage is a dangerous place due to the accumulation of reactive oxygen species (ROS), which can perturb cytoplasmic oxidative balance. Macrophage activation through monocyte recruitment in tissues occurs in a highly regulated manner upon detection of microbial pathogen-associated molecular patterns (PAMPs), such as the Gram-negative bacterial cell wall component lipopolysaccharide (LPS), stimulating ROS production. ROS can be generated from many cellular processes, either directly or as a result of incomplete reduction of free radicals (1). One of the main sources of ROS is the NADPH oxidase (NOX), a specialized transmembrane protein complex that generates superoxide (O2–), which has been implicated in several inflammatory diseases (2). The generation of ROS can also stem from the mitochondrial electron transport chain, due to insufficient reduction of superoxide anions. Another source is the inducible form of nitric oxide synthase 2 (iNOS). iNOS produces nitric oxide from L-arginine and is known to play key roles in macrophage function (3,4).

Depolarising levels of KCl inhibit endothelin-1-mediated release of arachidonic acid in rat C6 glioma cells

Conference Article| May 01 1995 Depolarising levels of KCl inhibit endothelin-1-mediated release of arachidonic acid in rat C6 glioma cells D.J. Dunican; D.J. Dunican 1Biochemistry Department, Trinity College, Dublin 2, Ireland Search for other works by this author on: This Site PubMed Google Scholar R. Griffiths; R. Griffiths 1Biochemistry Department, Trinity College, Dublin 2, Ireland*Division of Biochemistry, Irvine Building, North St., St. Andrews KY16 9AI, UK Search for other works by this author on: This Site PubMed Google Scholar L.A.J. O'Neill; L.A.J. O'Neill 1Biochemistry Department, Trinity College, Dublin 2, Ireland Search for other works by this author on: This Site PubMed Google Scholar D.C. Williams D.C. Williams 1Biochemistry Department, Trinity College, Dublin 2, Ireland Search for other works by this author on: This Site PubMed Google Scholar Biochem Soc Trans (1995) 23 (2): 285S. https://doi.org/10.1042/bst023285s Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share MailTo Twitter LinkedIn Cite Icon Cite Get Permissions Citation D.J. Dunican, R. Griffiths, L.A.J. O'Neill, D.C. Williams; Depolarising levels of KCl inhibit endothelin-1-mediated release of arachidonic acid in rat C6 glioma cells. Biochem Soc Trans 1 May 1995; 23 (2): 285S. doi: https://doi.org/10.1042/bst023285s Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsBiochemical Society Transactions Search Advanced Search Keywords: CNS, central nervous system, Et-1, endothelin, AA, arachidonate, PKC, protein kinase C, PLA2, phospholipase A2 This content is only available as a PDF. © 1995 Biochemical Society1995 Article PDF first page preview Close Modal You do not currently have access to this content.

NT-3

No abstract is provided for this article.

The Toll/interleukin-1 receptor domain: a molecular switch for inflammation and host defence

The pro-inflammatory cytokine interleukin-1 (IL-1) signals via the Type-1 IL-1 receptor (IL-1RI), inducing an increase in the expression of many genes with roles in immunity and inflammation. The signalling pathways involve two adapter proteins, MyD88 and Tollip, which via two IL-1 receptor-associated kinases (IRAK and IRAK-2) activate transcription factors such as nuclear factor-κB and protein kinases such as p38 mitogen-activated protein kinase. A role for the low-molecular-mass G-proteins Rac, Ras and Rap in these processes has also been indicated. IL-1RI is the founder of a diverse superfamily of receptors, which all share a cytosolic domain, termed the Toll/IL-1 receptor (TIR) domain. The superfamily can be divided broadly into three subgroups. The first of these is most similar to IL-1RI and includes the receptor for IL-18 and the Th2 cell regulator T1/ST2. The second subgroup is most similar to the Drosophila melanagaster protein Toll and includes Toll-like receptor 2 (TLR2), which is required for host defence against Gram-positive bacteria and fungi, and TLR4, which is required for lipopolysaccharide responsiveness, and thus is involved in host defence against Gram-negative bacteria. There are also a number of TLRs in plants and insects, all involved in host defence. The third subgroup contains nonreceptor proteins which possess a TIR domain and are cytosolic. MyD88 is a member, and it presumably complexes with IL-1RI via a TIR-TIR interaction. The other two members are proteins encoded by the vaccinia virus, A46R and A52R, which block TIR-dependent signalling. This receptor superfamily therefore appears to play a central role in inflammation and host defence against infection, pointing to the TIR domain as a critical molecular player in the innate immune response.

High-Resolution Structure of Murine Interleukin 1 Homologue IL-1F5 Reveals Unique Loop Conformations for Receptor Binding Specificity^,

Interleukin-1 (IL-1) F5 is a novel member of the IL-1 family. The IL-1 family are involved in innate immune responses to infection and injury. These cytokines bind to specific receptors and cause activation of NFkappaB and MAP kinase. IL-1F5 has a sequence identity of 44% to IL-1 receptor antagonist (IL-1Ra), a natural antagonist of the IL-1 system. Here we report the crystal structure of IL-1F5 to a resolution of 1.6 A. It has the same beta-trefoil fold as other IL-1 family members, and the hydrophobic core is well conserved. However, there are substantial differences in the loop conformations, structures that confer binding specificity for the cognate receptor to IL-1beta and the antagonist IL-1Ra. Docking and superimposition of the IL-1F5 structure suggest that is unlikely to bind to the interleukin1 receptor, consistent with biochemical studies. The structure IL-1F5 lacks features that confer antagonist properties on IL-1Ra, and we predict that like IL-1beta it will act as an agonist. These studies give insights into how distinct receptor specificities can evolve within related cytokine families.

In vitro protocol demonstrating five functional steps of trained immunity in mice: Implications on biomarker discovery and translational research

We developed an in vitro methodology to study trained immunity using murine bone-marrow-derived macrophages stimulated with β-glucan and lipopolysaccharide (LPS). Longitudinal analysis of interleukin (IL)-6 and tumor necrosis factor (TNF) production demonstrates that trained macrophages secrete higher cytokine levels following primary stimulation with β-glucan compared to unstimulated macrophages (step 1). After a resting period, trained macrophages return to basal levels of cytokine production (step 2) but rapidly produce enhanced levels of IL-6 and TNF after secondary stimulation with LPS, compared to macrophages individually stimulated with either β-glucan (step 3) or LPS (step 4) alone. The combined cytokine production of macrophages after single stimulation with β-glucan (stimulus 1) and LPS (stimulus 2) is significantly lower than the cytokine levels produced by trained macrophages sequentially stimulated with both β-glucan and LPS (stimulus 1 + 2) (step 5). These results experimentally reproduce the distinctive functional stages that macrophages undergo during the training process.

Influenza A virus causes maternal and fetal pathology via innate and adaptive vascular inflammation in mice

Significance Influenza infection during pregnancy is associated with increased maternal and perinatal complications. Here, we show that, during pregnancy, influenza infection leads to viral dissemination into the aorta, resulting in a peripheral “vascular storm” characterized by enhanced inflammatory mediators; the influx of Ly6C monocytes, neutrophils, and T cells; and impaired vascular function. The ensuing vascular storm induced hypoxia in the placenta and fetal brain and caused an increase in circulating cell free fetal DNA and soluble Flt1 release. We demonstrate that vascular dysfunction occurs in response to viral infection during pregnancy, which may explain the high rates of morbidity and mortality in pregnant dams, as well as the downstream perinatal complications associated with influenza infection.

Keeping infectious complications at bay with immunonutrition

Certain nutrients have been shown to influence immunological and inflammatory responses in humans, and a new term, immuno-nutrition, has been coined for the study of foodstuffs complimented with substances that might enhance immunity. This concept is being used by several food companies to promote their products, both for humans and household pets. Whether immunonutrition translates into quantifiable changes in immunity during illness is uncertain still. A recent report by D. Heyland and colleagues at the Kingston General Hospital in Canada analyzed systematically a total of 2419 patients in 22 randomized trials, which compared the use of immunonutrition with standard enteral nutrition in surgical and critically ill patients. The studies involved enteral nutrition supplemented with some combination of arginine, glutamine, nucleotides and omega-3 fatty acids compared with standard nutrition. The outcomes measured included infectious complications and mortality rates. The authors found that the use of commercial formulations with high arginine content was associated with a significant reduction in infectious complications, and a trend towards a lower mortality rate compared with other ‘immune-enhancing’ diets, particularly in surgical patients, rather than in the critically ill. They conclude that the studies suggest immunonutrition might decrease infectious complications but is not associated with an overall advantage in terms of mortality. J. Am. Med. Assoc. (2001) 286, 944–953 LON

Metabolic regulation of <scp>NLRP</scp>3

Summary A shift in our understanding of macrophage biology has come about as a result of recent discoveries in the area of metabolic reprogramming of macrophages. The NLRP 3 inflammasome drives the activation of caspase‐1, leading to the production of IL ‐1β, IL ‐18, and a type of cell death termed pyroptosis. The NLRP 3 inflammasome has been shown to sense metabolites such as palmitate, uric acid, and cholesterol crystals and is inhibited by ketone bodies produced during metabolic flux. The NLRP 3 inflammasome has also been shown to be regulated by mitochondrial reactive oxygen species and components of glycolysis, such as Hexokinase. Here, we review these findings and discuss their importance for inflammation and furthermore discuss potential therapeutic benefits of targeting NLRP 3.

2009 Editorial Board

No abstract is provided for this article.

NLRP3 has a protective role in age-related macular degeneration through the induction of IL-18 by drusen components

No abstract is provided for this article.

IL-4

No abstract is provided for this article.

Inflammasomes in inflammatory disorders: the role of TLRs and their interactions with NLRs

No abstract is provided for this article.

Caspase-4: A Therapeutic Target for Peptic Ulcer Disease

Peptic ulcers are caused by the interaction between bacterial and host factors. This study demonstrates enhanced expression of caspase-4 in peptic ulcer patient biopsies, indicating that pyroptosis and noncanonical inflammasome activity may be processes involved in peptic ulcer disease. We show that primary murine macrophages infected with Helicobacter pylori upregulate caspase-11 (the ortholog of human caspase-4), activate caspase-1, and secrete IL-1β. We demonstrate that misoprostol (a stable PGE1 analogue) decreased IL-1β secretion and delayed lethality in vivo in a murine peritonitis model. PGE2 was shown to inhibit caspase-11–driven pyroptosis and IL-1β secretion in macrophages. Overall, we provide evidence for a pathological role of caspase-4/11 in peptic ulcer disease and propose that targeting caspase-4 or inhibiting pyroptosis may have therapeutic potential in the management of peptic ulcers.

Eotaxin 1

No abstract is provided for this article.

Apo2L

No abstract is provided for this article.

IL-9

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

TRIF [TIR (Toll/interleukin-1 receptor) domain-containing adaptor protein inducing interferon β; 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 stimuli, such as the ligands for TLR2, TLR3 and TLR4, and by the pro-inflammatory cytokines tumour necrosis factor α and interleukin-1α. All of these stimuli act via an NF-κB (nuclear factor-κB) motif at position −127. In spite of the presence of a STAT1 (signal transduction and activators of transcription 1) motif at position −330, the addition of type I or type II interferon had no effect on TRIF activity. The human TRIF gene would therefore appear to be regulated primarily by NF-κB.