A5017150636- Immune Response and Inflammation
- Inflammasome and immune disorders
- Bacterial Infections and Vaccines
- Antimicrobial Peptides and Activities
- interferon and immune responses
- Immune Cell Function and Interaction
- NF-κB Signaling Pathways
- Reproductive tract infections research
- Neonatal Respiratory Health Research
- Lipid Membrane Structure and Behavior
- IL-33, ST2, and ILC Pathways
- Cell death mechanisms and regulation
- RNA regulation and disease
- Cytomegalovirus and herpesvirus research
- Immune cells in cancer
- Immunotherapy and Immune Responses
- Complement system in diseases
- Veterinary medicine and infectious diseases
- Galectins and Cancer Biology
- Streptococcal Infections and Treatments
- Cancer-related molecular mechanisms research
- Malaria Research and Control
- Neonatal and Maternal Infections
- Fatty Acid Research and Health
- RNA Interference and Gene Delivery
University of Massachusetts Chan Medical School
2007-2023
University of Bonn
2013-2016
University Hospital Bonn
2013-2016
Noble (United States)
2010
Office of Infectious Diseases
2010
Boston Medical Center
1992-2001
Boston University
1992-2001
Merck & Co., Inc., Rahway, NJ, USA (United States)
1997
Rockefeller University
1997
XOMA (United States)
1997
Abstract The IL-1 family cytokines are regulated on transcriptional and posttranscriptional levels. Pattern recognition cytokine receptors control pro-IL-1β transcription whereas inflammasomes regulate the proteolytic processing of pro-IL-1β. NLRP3 inflammasome, however, assembles in response to extracellular ATP, pore-forming toxins, or crystals only presence proinflammatory stimuli. How activation gene by signaling enables remains elusive controversial. In this study, we show that cell...
Toll–IL-1–resistance (TIR) domain–containing adaptor-inducing IFN-β (TRIF)–related adaptor molecule (TRAM) is the fourth TIR protein to be described that participates in Toll receptor signaling. Like TRIF, TRAM activates interferon regulatory factor (IRF)-3, IRF-7, and NF-κB-dependent signaling pathways. Toll-like (TLR)3 4 activate these pathways induce IFN-α/β, regulated on activation, normal T cell expressed secreted (RANTES), γ interferon–inducible 10 (IP-10) expression independently of...
A New Linc in Innate Immunity Long noncoding RNAs (lncRNAs) have recently emerged as important regulators of gene expression a wide variety biological processes, although specific roles for these molecules the immune system not been described. Carpenter et al. (p. 789 , published online 1 August) now define function one such lncRNA system, lincRNA-Cox2. Whole-transcriptome profiling revealed that lincRNA-Cox2 was induced mouse macrophages response to activation Toll-like receptors—molecules...
Lipopolysaccharide (LPS) is the main inducer of shock and death in Gram-negative sepsis. Recent evidence suggests that LPS-induced signal transduction begins with CD14-mediated activation 1 or more Toll-like receptors (TLRs). The lipid A analogues IVa Rhodobacter sphaeroides (RSLA) exhibit an uncommon species-specific pharmacology. Both compounds inhibit effects LPS human cells but display LPS-mimetic activity hamster cells. We transfected TLR4 TLR2 into fibroblasts to determine if either...
Abstract The paramyxovirus Sendai (SV), is a well-established inducer of IFN-αβ gene expression. In this study we show that SV induces expression normally in cells from mice with targeted deletions the Toll-IL-1 resistance domain containing adapters MyD88, Mal, Toll/IL-1R domain-containing adaptor inducing IFN-β (TRIF), and TRIF-related molecule TLR3, or E3 ubiquitin ligase, TNFR-associated factor 6. This TLR-independent induction after infection replication dependent mediated by RNA...
Hemozoin (HZ) is an insoluble crystal formed in the food vacuole of malaria parasites. HZ has been reported to induce inflammation by directly engaging Toll-like receptor (TLR) 9, endosomal receptor. "Synthetic" (beta-hematin), typically generated from partially purified extracts bovine hemin, structurally identical natural HZ. When HPLC-purified hemin was used synthesize crystal, beta-hematin had no inflammatory activity. In contrast, Plasmodium falciparum cultures a potent TLR9 inducer....
Mammalian responses to LPS require the expression of Toll-like receptor 4 (TLR4), CD14, and MD-2. We expressed fluorescent TLR4 in cell lines found that densely localized surface Golgi. Similar distributions were observed human monocytes. Confocal imaging revealed rapid recycling TLR4-CD14-MD-2 complexes between Golgi plasma membrane. Fluorescent followed these trafficking pathways CD14-positive cells. The TLR4- adapter protein, MyD88, translocated upon exposure, cross-linking with antibody...
Abstract Vascular disrupting agents such as 5,6-dimethylxanthenone-4-acetic acid (DMXAA) represent a novel approach for cancer treatment. DMXAA has potent antitumor activity in mice and, despite significant preclinical promise, failed human clinical trials. The of been linked to its ability induce type I IFNs macrophages, although the molecular mechanisms involved are poorly understood. In this study, we identify stimulator IFN gene (STING) direct receptor leading TANK-binding kinase 1 and...
Somatic cell mutagenesis is a powerful tool for characterizing receptor systems. We reported previously two complementation groups of mutant lines derived from CD14-transfected Chinese hamster ovary--K1 fibroblasts defective in responses to bacterial endotoxin. Both classes mutants expressed normal gene product Toll-like (TLR)4, and fully responded stimulation by tumor necrosis factor (TNF)-alpha or interleukin (IL)-1 beta. identified the lesion one MD-2, putative TLR4 coreceptor. The...
TRIF-related adaptor molecule (TRAM) is the fourth Toll/IL-1 resistance domain-containing to be described that participates in Toll-like receptor (TLR) signaling. TRAM functions exclusively TLR4 pathway. Here we show by confocal microscopy localized plasma membrane and Golgi apparatus, where it colocalizes with TLR4. Membrane localization of result myristoylation because mutation a predicted site (TRAM-G2A) brought about dissociation from its relocation cytosol. Further, TRAM, but not...
Three cell-surface proteins have been recognized as components of the mammalian signaling receptor for bacterial lipopolysaccharide (LPS): CD14, Toll-like receptor-4 (TLR4), and MD-2. Biochemical visual studies shown here demonstrate that role CD14 in signal transduction is to enhance LPS binding MD-2, although its expression not essential cellular activation. These clarify how MD-2 functions: we found enables TLR4 allows formation stable complexes. must be bound on cell surface before can...
Toll-like receptor (TLR) 2 and TLR4 have been implicated in the responses of cells to LPS (endotoxin). CD14-transfected Chinese hamster ovary (CHO)-K1 fibroblasts (CHO/CD14) are exquisitely sensitive endotoxin. Sequence analysis CHO-TLR2, compared with human mouse TLR2, revealed a single base pair deletion. This frameshift mutation resulted an alternative stop codon, encoding protein devoid transmembrane intracellular domains. CHO-TLR2 cDNA failed enable signaling upon transient transfection...
Abstract Gram-negative bacteria and the LPS constituent of their outer membranes stimulate release inflammatory mediators believed to be responsible for clinical manifestations septic shock. The GPI-linked membrane protein, CD14, initiates signaling cascade induction this response by LPS. In paper, we report generation characterization CD14-null mice in which entire coding region CD14 was deleted. As expected, failed elicit TNF-α IL-6 production macrophages taken from these animals, loss...
We screened 29 strains of Neisseria gonorrhoeae and found 16/21 that resisted killing by normal human serum 0/8 sensitive bound the complement regulator, C4b-binding protein (C4bp). Microbial surface–bound C4bp demonstrated cofactor activity. constructed gonococcal with hybrid porin (Por) molecules derived from each major serogroups (Por1A Por1B) N. gonorrhoeae, showed loop 1 Por1A is required for binding. Por1B loops 5 7 serum-resistant gonococci together formed a negatively charged...
The alginate capsule produced by the human pathogen Pseudomonas aeruginosa is composed mainly of mannuronic acid polymers (poly-M) that have immunostimulating properties. Poly-M shares with lipopolysaccharide ability to stimulate cytokine production from monocytes in a CD14-dependent manner. In present study we examined role Toll-like receptor (TLR) 2 and TLR4 responses poly-M. Blocking antibodies TLR2 partly inhibited tumor necrosis factor induced poly-M monocytes, further inhibition was...
Abstract A critical component of innate immune response to infection and tissue damage is the NACHT, LRR, PYD domains–containing protein 3 (NLRP3) inflammasome, this pathway its activation products have been implicated in pathophysiology a variety diseases. NLRP3 inflammasome leads cleavage pro–IL-1β pro–IL-18, as well subsequent release biologically active IL-1β, IL-18, other soluble mediators inflammation. In study, we further define pharmacology previously reported inflammasome–selective,...
Inflammasome activation is associated with numerous diseases. However, in vivo detection of the activated inflammasome complex has been limited by a dearth tools. We have developed transgenic mice that ectopically express fluorescent adaptor protein, apoptosis-associated speck-like protein containing caspase recruitment domain (ASC) and characterized formation assembled complexes ("specks") primary cells tissues. In addition to hematopoietic cells, we found stromal population lung tissues...