A5077276012- Immune Response and Inflammation
- Immune cells in cancer
- Neuroinflammation and Neurodegeneration Mechanisms
- NF-κB Signaling Pathways
- Amyotrophic Lateral Sclerosis Research
- Protease and Inhibitor Mechanisms
- Immune Cell Function and Interaction
- Alzheimer's disease research and treatments
- Microtubule and mitosis dynamics
- Peptidase Inhibition and Analysis
- Antimicrobial Peptides and Activities
- Glycosylation and Glycoproteins Research
- Inflammation biomarkers and pathways
- Cell Adhesion Molecules Research
- Macrophage Migration Inhibitory Factor
- Cytokine Signaling Pathways and Interactions
- Asthma and respiratory diseases
- Mitochondrial Function and Pathology
- S100 Proteins and Annexins
- Vitamin K Research Studies
- RNA and protein synthesis mechanisms
- Eicosanoids and Hypertension Pharmacology
- Phagocytosis and Immune Regulation
- Signaling Pathways in Disease
- ATP Synthase and ATPases Research
Cornell University
2005-2016
National Institute of Infectious Diseases
2009
Bipar
2007
Memorial Sloan Kettering Cancer Center
1999
Abstract The capacity of 12 cytokines to induce NO2- or H2O2 release from murine peritoneal macrophages was tested by using resident macrophages, elicited with periodate, casein, thioglycollate broth. Elevated in response PMA observed after a 48-h incubation IFN-gamma, TNF-alpha, TNF-beta, CSF-GM. Of these, only IFN-gamma induced substantial secretion during the culture period. inactive both assays under conditions were IL-1 beta, IL-2, IL-3, IL-4, IFN-alpha, IFN-beta, CSF-M, and...
Nitric oxide (NO) conveys a variety of messages between cells, including signals for vasorelaxation, neurotransmission, and cytotoxicity. In some endothelial cells neurons, constitutive NO synthase is activated transiently by agonists that elevate intracellular calcium concentrations promote the binding calmodulin. contrast, in macrophages, activity appears slowly after exposure to cytokines bacterial products, sustained, functions independently A monospecific antibody was used clone...
In response to bacterial endotoxin (e.g., LPS) or endogenous proinflammatory cytokines TNF and IL-1β), innate immune cells release HMGB1, a late cytokine mediator of lethal endotoxemia sepsis. The delayed kinetics HMGB1 makes it an attractive therapeutic target with wider window opportunity for the treatment systemic inflammation. However, receptor(s) responsible HMGB1-mediated production has not been well characterized. Here we demonstrate that in human whole blood, neutralizing antibodies...
The growth factor progranulin (PGRN) has been implicated in embryonic development, tissue repair, tumorigenesis, and inflammation, but its receptors remain unidentified. We report that PGRN bound directly to tumor necrosis (TNFRs) disturbed the TNFα-TNFR interaction. PGRN-deficient mice were susceptible collagen-induced arthritis, administration of reversed inflammatory arthritis. Atsttrin, an engineered protein composed three fragments, exhibited selective TNFR binding. Atsttrin prevented...
Sarm-Assisted Suicide Neurodegenerative disease or nerve lesions cause axons and synapses to disintegrate through a process known as Wallerian degeneration, which may involve an active “axon death program.” Osterloh et al. (p. 481 , published online 7 June; see the Perspective by Yu Luo ) identify loss-of-function mutations in Drosophila dSarm that are capable of blocking degeneration severed for fly life span. Deletion mouse Sarm1 provides similar protection weeks after injury, suggests...
Abstract Macrophage deactivating factor (MDF) and three members of the transforming growth factor-beta family (TGF-beta 1, -beta 2, 3) blocked ability IFN-gamma to induce release reactive nitrogen intermediates from mouse peritoneal macrophages. Raising concentration did not diminish potency inhibitors (50% inhibition by approximately 7 nM MDF, 2 pM TGF-beta 4 8 3). These partially induction nitrite in macrophages activated with combination plus TNF-alpha, but were incapable inhibiting when...
Progranulin (PGRN) is a widely expressed protein involved in diverse biological processes. Haploinsufficiency of PGRN the human causes tau-negative, ubiquitin-positive frontotemporal dementia (FTD). However, mechanisms are unknown. To explore role vivo, we generated PGRN-deficient mice. Macrophages from these mice released less interleukin-10 and more inflammatory cytokines than wild type (WT) when exposed to bacterial lipopolysaccharide. failed clear Listeria monocytogenes infection as...
To explore regulation of potentially lethal responses to bacterial lipopolysaccharide (LPS), we used differential display under LPS-free conditions compare macrophage cell lines from two strains mice congenic for a locus affecting LPS sensitivity. LPS- hyporesponsive cells, primary macrophages, and polymorphonuclear leukocytes transcribed secretory leukocyte protease inhibitor (SLPI), known epithelial cell-derived serine proteases. Transfection macrophages with SLPI suppressed LPS-induced...
Bacterial lipopolysaccharide (LPS) exerts profound effects on mammalian hosts in part by inducing macrophages to release tumor necrosis factor-α (TNF-α); the mechanisms involved are unresolved. The microtubule stabilizer taxol shared two actions of LPS macrophages: it rapidly decreased TNF-α receptors and triggered release. Both were absent LPS-hyporesponsive C3H/HeJ mice. In recombinant inbred mice, genes controlling responses closely linked. Dexamethasone blocked both stimuli but did not...
Taxol can mimic bacterial lipopolysaccharide (LPS) by activating mouse macrophages in a cell cycle-independent, LPS antagonist-inhibitable manner. Macrophages from C3H/HeJ mice, which have spontaneous mutation Toll-like receptor 4 (TLR4), are hyporesponsive to both and Taxol, suggesting that may share signaling pathway involving TLR4. To determine whether TLR4 its interacting adaptor molecule MyD88 necessary for Taxol's mimetic actions, we examined responses of primary genetically defective...
The innate immune system relies on evolutionally conserved Toll-like receptors (TLRs) to recognize diverse microbial molecular structures. Most TLRs depend a family of adaptor proteins termed MyD88s transduce their signals. Critical roles MyD88-1-4 in host defense were demonstrated by defective responses knockout mice. In contrast, the sites expression and functions vertebrate MyD88-5 have remained elusive. We show that is distinct from other preferentially expressed neurons, colocalizes...
Taxol, a plant-derived antitumor agent, stabilizes microtubules. Taxol also elicits cell signals in manner indistinguishable from bacterial lipopolysaccharide (LPS). LPS-like actions of are controlled by the lps gene and independent binding to known target, β-tubulin. Using biotin-labeled avidin-agarose affinity chromatography, peptide mass fingerprinting, we identified two targets mouse macrophages brain as heat shock proteins (Hsps) 70- 90-kDa families. Geldanamycin, specific inhibitor Hsp...
Brains from subjects who have Alzheimer's disease (AD) express inducible nitric oxide synthase (iNOS). We tested the hypothesis that iNOS contributes to AD pathogenesis. Immunoreactive was detected in brains of mice with AD-like resulting transgenic expression mutant human beta-amyloid precursor protein (hAPP) and presenilin-1 (hPS1). bred hAPP-, hPS1-double be iNOS(+/+) or iNOS(-/-), compared them a congenic WT strain. Deficiency substantially protected premature mortality, cerebral plaque...
Progranulin haploinsufficiency causes frontotemporal dementia with tau-negative, ubiquitin-positive neuronal inclusion pathology. In this study, we showed that progranulin-deficient mice displayed increased depression- and disinhibition-like behavior, as well deficits in social recognition from a relatively young age. These did not have any deficit locomotion or exploration. Eighteen-month-old demonstrated impaired spatial learning memory the Morris water maze. addition to behavioral...
Results Allergic SLPI transgenic mice showed a significant decrease in airway resistance compared to wild-type (6.3 ± 1.1 vs. 8.0 2.1 cm H20 × s/ml, p < 0.001), the same effect was observed with inflammatory cell infiltration, eosinophil percentage (24 1.1% 29 2.3%, goblet cells (6 1.4 36 4.0%, 0.001) lungs and IgE levels (2014.1 309.2 4173.2 685.6 ng/ml, plasma. knock-out displayed significantly higher values mice. They include lung (8.6 2.7 6.6 0.5 H20*s/ml, influx, eosinophils (36.0 29.0...
Taxol, a naturally occurring diterpene with antitumor activity, induces tubulin polymerization to generate abnormally stable and nonfunctional microtubules. Previously, we showed that taxol has lipopolysaccharide (LPS)-like effects on macrophages. As LPS is potent inducer of macrophage cytokine production, investigated whether similar effect exerted by taxol. In dose-dependent manner, LPS-free induced release biologically active tumor necrosis factor alpha (TNF) inflammatory murine...
Macrophages are activated from a resting state by combination of cytokines and microbial products. Microbes often sensed through Toll-like receptors signaling MyD88. We used large-scale microarrays in multiple replicate experiments followed stringent statistical analysis to compare gene expression wild-type (WT) MyD88-/- macrophages. confirmed key results quantitative reverse transcription polymerase chain reaction, Western blot, enzyme-linked immunosorbent assay. Surprisingly, many genes,...
The effect of bacterial lipopolysaccaride (LPS) on macrophage receptors for tumor necrosis factor/ cachectin (TNF-R) was studied.At equilibrium, iodinated recombinant human TNFa (rTNFa) bound to 1100 f 200 sites/cell macrophage-like RAW 264.7 cells with a K d 1.3 0.1 X lo-' M. Preexposure 10 ng/ml LPS 1 h at 37 "C resulted in complete loss cell surface binding sites.50% ensued after 0.6 LPS, or 15 min LPS.Complete sites occurred without change numbers complement receptor type 3.No decrease...
Exposure of murine and human macrophages umbilical vein endothelial cells to micromolar concentrations five microtubule (MT)-depolymerizing agents (colchicine, nocodazole, podophyllotoxin, vincristine, vinblastine) resulted in a loss binding sites for iodinated TNF-alpha. The reduction amounted 40-60% by 1 h approximately 75% 2-4 h. In h, specific was reduced 50% 0.1-5 microM these drugs at 37 degrees C, but not 4 C. Inactive isomers colchicine were ineffective, as...